Michael Rubinstein, Ph.D, - US grants

9409787 Rubinstein This is an United States-Russia Joint Cooperative Research grant funded jointly by the Division of Materials Research and the Division of International Programs. Professor Michael Rubinstein of the University of Rochester and Eastman Kodak Company will collaborate with Professor Alexander Semenov of Moscow State University. Theoretical research will be conducted on the staic and dynamic properties of heteropolymers with strongly interacting groups including block copolymers in selective solvents, ionomers and associating polymers. These systems have a number of unique structural, mechanical and rheological properties. Each research group has complementary skills to study these materials. %%% ***

This three-year award will support U.S.-France cooperative research in polymers and biophysics and involves Sergei Obukhov of the University of Florida, Michael Rubinstein of Kodak and Jean-Louis Viovy of the Ecole Superieure for Industrial Physics and Chemistry, Paris, France. They propose a study of DNA gel electrophoresis, which is the basic method for DNA separation. The objectives of their research are (1) to develop a detailed understanding of the structure of a DNA molecule moving through a gel in a strong electric field; and (2) to improve separation techniques of long chain DNA molecules. They will work on a set of analytical and closely related numerical models which allow simulation of the motion of ultra large DNA molecules. The models will be tested against other numerical models and experiments developed by the French investigators. The U.S. investigators bring to this collaboration considerable expertise in polymer theory and physics. This is complemented by Dr. Viovy's expertise in molecular modeling and the experiments in DNA electrophoresis currently in progress in Paris. Their research addresses the ultimate goal of improving the accuracy and efficiency of current DNA separation techniques. These improved techniques are essential for mapping the `human genome` and for advancements in molecular biology and bioengineering.

9730777 Rubinstein Charged polymers have recently attracted much attention due to their unique properties and their technological importance as rheology modifiers, dispersing aids, stabilizers, gelling agents, binders, etc. Polyampholytes are polymers carrying both positive and negative charges. Polymers carrying only positive or negative charge are called polyelectrolytes. The net charge of polyampholytes, e.g., proteins, is determined by the pH of the aqueous solution. Long-range Coulomb interactions are responsible for the rich behavior of these polymeric systems and for the difficulties in developing theories to describe them. While the coherent picture of polyelectrolytes and their interactions with surfaces is beginning to emerge, the theoretical description of polyampholytes is lagging far behind. In particular, there is no satisfactory theory of polyampholyte adsorption. Such a theory is necessary for understanding the details of interactions of latex particles stabilized by polyampholytes, adsorption of proteins on cell membranes, complexation of polyampholytes with polyelectrolytes and related problems. In the current research both analytical and numerical models of polyampholyte adsorption on charged surfaces will be constructed and solved. The problems addressed will include: the adsorption of a single polyampholyte chain, multi-chain adsorption, and the kinetics of polyampholyte adsorption. %%% Charged polymers have recently attracted much attention due to their unique properties and their technological importance as rheology modifiers, dispersing aids, stabilizers, gelling agents, binders, etc. Polyampholytes are polymers carrying both positive and negative charges. Polymers carrying only positive or negative charge are called polyelectrolytes. The net charge of polyampholytes, e.g., proteins, is determined by the pH of the aqueous solution. Long-range Coulomb interactions are responsible for the rich behavior of these polymeric systems and for the difficulties in developing theories to describe them. While the coherent picture of polyelectrolytes and their interactions with surfaces is beginning to emerge, the theoretical description of polyampholytes is lagging far behind. In particular, there is no satisfactory theory of polyampholyte adsorption. Such a theory is necessary for understanding the details of interactions of latex particles stabilized by polyampholytes, adsorption of proteins on cell membranes, complexation of polyampholytes with polyelectrolytes and related problems. In the current research both analytical and numerical models of polyampholyte adsorption on charged surfaces will be constructed and solved. The problems addressed will include: the adsorption of a single polyampholyte chain, multi-chain adsorption, and the kinetics of polyampholyte adsorption. ***

0102267
Rubinstein
This award supports theoretical and computational research on charged polymer adsorption at surfaces and interfaces. Research will focus on hydrophilic and hydrophobic polyelectrolytes. The PI will develop an analytical model of adsorption of hydrophilic polyelectrolytes in the presence of short-range and long-range interactions between polymers and surfaces. De Gennes' self-similar carpet model of short-range adsorption of uncharged polymers will be combined with a model of long-range adsorption of polyelectrolytes to oppositely charged surfaces. Another model will be developed to study hydrophobic polyelectrolyte adsorption in the presence of both short-range and long-range interactions. The properties of hydrophobic polyelectrolytes in solution will be studied in more detail to enable the extension of adsorption models to hydrophobic polyelectrolytes. The interplay of short-range attraction and long-range (electrostatic) repulsion leads to a necklace conformation of hydrophobic polyelectrolytes. Computer simulations and scattering experiments have recently confirmed the main features of the necklace model of hydrophobic polyelectrolytes. The remaining open questions important for the application of the model to the adsorption of hydrophobic polyelectrolytes will be investigated using a combination of analytical calculations and computer simulations. The resulting model of hydrophobic polyelectrolyte solutions will be combined with the adsorption model of hydrophilic polyelectrolytes into an adsorption model of hydrophobic polyelectrolytes.
The kinetic theory of polyelectrolyte adsorption at charged surfaces will be developed using de Gennes' two-step approach in the framework of Rouze-Zimm model for unentangled adsorbed layers and of tube models for entangled layers. A wide range of educational activities spanning K-12 outreach to the education of postdoctoral research associates are supported by this grant. This award also provides partial support of the preparation of a polymer physics textbook.
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This award supports theoretical and computational research that contributes toward the development of a complete molecular picture of the adsorption of charged polymers on charged surfaces. Adsorption of charged polymers is one of the least understood areas of polymer physics. The technological importance of charged polymers as rheology modifiers, dispersing aids, stabilizers, and binders is due to their unique properties both in solutions and near surfaces. An application in the area of nanoscale science and engineering is multilayer formation via layer-by-layer deposition of oppositely charged polyelectrolytes, leading to novel methods of nanodevice fabrication. A better understanding of charged polymers will also impact molecular biophysics because many biopolymers, such as DNA and proteins, are charged, and electrostatics plays a significant role in their properties and function. The award will also support a wide range of educational activities including K-12 outreach and education in polymer physics and chemistry at the undergraduate, graduate, and postdoctoral levels. Some of the research will be included in the Polymer Physical Chemistry course sequence at UNC and in a textbook that is in preparation.
***

0103307
Sheiko

This proposal was submitted in response to the solicitation "Nanoscale Science and Engineering" (NSF 00-119). Miniature actuators, which produce large strains at short response times are of interest for nano- and biotechnologies. They can be used to construct micro fluidic pumps, tiny locomotives, and micromanipulators. It is generally believed that extremely efficient and fast actuators can be prepared from single macromolecules. Cylindrical brush molecules consisting of a flexible backbone and densely grafted side chains are possible candidates because they can change their length in response to variations in their surrounding environment and the effect of an external field. It is proposed to use soft cylinders with a stimuli-responsive shape as a multifunctional platform for the development of nanomechanical devices. One of the most interesting applications is envisioned for an array of molecular brushes, which are tethered with one end to a solid substrate and change their conformation under incident light. The layers will be designed to generate surface-relief-gratings, which propagate along the substrate plane and transport different fluids, small particles, and ultimately biological cells. For this purpose, either IR-absorber dyes or photosensitive azobenzene and spiropyran moieties will be introduced in the chemical structure of brushes. Similar to tracheal cilia, the tethered molecules will beat back and forth in a coordinated way and propel overlaying substances in a certain direction.

The project will address three fundamental questions:

(i) What are the molecular and external parameters controlling the length of brush molecules?

(ii) What is the force developed during contraction/extension of brush molecules?

(iii) What are the dynamic properties of the tethered brushes under the effect of polarized light?

The PI's will achieve their goals of answering these important questions by taking the following steps. First, they will prepare a series of well-defined brushes and investigate the specific effects of the side chain length, the grafting density, and the photoisomerizable groups on the length of brush molecules. Second, they will study mechanical properties of individual molecules and tethered monolayers by stretching them uniaxially with an atomic force microscope and magnetic tweezers. The experimental studies will be supported by theoretical analysis of brush conformations. Third, an optical set-up combined with an atomic force microscope will be built for in-situ investigation of the morphology and the diffraction efficiency of the surface relief grating. This will allow the measurement of the access and relaxation times of the double-brush monolayer, and the monitoring of the transport of the overlaying substances.

This interdisciplinary project will be based on precise chemistry, rigorous physics, and biological concepts. It presents a perfect opportunity for students to master several of these fundamental disciplines and at the same time gain experience at the cutting edge of nanotechnology.

The Principal Investigators will acquire dedicated instrumentation for computational research in structural biology, material science, and environmental/marine sciences. The investigators also lead the undergraduate & graduate computational science curricula at UNC-Chapel Hill, which will benefit from the proposed instrumentation. The proposed equipment includes clusters of linux workstations, two 16-processor beowulf-class machines for parallel programming development and education, and a next generation mid-sized shared memory machine|a 48 processor SGI Origin 3000. These three components will be integrated using campus optical fiber, and shared file and processing systems, with consistent configuration and portability across the six departments (Chemistry, Computer Science, Environmental Sciences and Engineering, Marine Science, Mathematics, Statistics) and the Institute for Marine Sciences (IMS). High-end production work will continue to be accomplished at the nearby North Carolina Supercomputing Center, which include a tera op IBM SP system with 180 nodes and 720 processors. The proposed instrumentation, along with the NCSC facility, will yield a high-performance computational environment for the interdisciplinary computational science research and education program at UNC-CH.

The investigator is studying the statistical properties of zeros and values of
L-functions in the context of random matrix theory. Random matrix models are
being used to conjecture the full asymptotic expansion and analytic continuation
for the moments of L-functions, and to make predictions for the statistical behavior
of ranks of elliptic curves. A C++ L-function class library along with a front end
application is also being developed for computing zeros and values of L-functions.
This software is being used by the investigator to numerically confirm the predictions
being made, and will be released freely to the public as a much needed tool for studying L-functions.
Many problems in number theory can be described in terms of the properties of
so-called L-functions. These functions, which encode profound information about various
number theoretic problems, have remained largely unyielding to mathematical analysis.
Many deep problems in number theory would be solved if one could understand these
functions in detail. Surprisingly, a seemingly unrelated field known as random matrix theory, a subject that originally arose in connection to experimental physics, has recently been found by number theorists and physicists alike to provide a framework in which to model the behavior of L-functions. This mysterious connection has been used successfully to make hitherto unimaginable predictions for the behavior of L-functions. The work in this proposal is concerned with exploring the connections between these two fields, number theory and random matrix theory. To assist in this project, the investigator is also preparing a software package, to be made freely available to the public, for numerically studying L-functions.
This award is being cofunded by the Algebra, Number Theory, and Combinatorics Program, the Numeric, Symbolic, and Geometric Computation Program, and the Computational Mathematics Program.

Michael Rubinstein of the University of North Carolina at Chapel Hill is supported by an award from the Theoretical and Computational Chemistry program for research which is developing a molecular model of the lung airway surface layer (ASL) which protects the body from inhaled substances. This research involves the combination of scaling theory, computer simulations, and self consistent field calculations to develop a set of predictive tools to describe various properties of the ASL. The main ingredients of the theory are coarse grained molecular models of two types of mucins. The first type, gel-forming mucins, are being modeled as a highly charged molecular brush with many associating domains per chain by combining the PI's recent theories of polyelectrolytes and solutions of associating polymers. Molecules of the second type, mucins with transmembrane domains, are being represented by polyelectrolyte molecular brushes with a group at one end that has a strong attraction to the cell membrane. The work is being carried out in collaboration with the Cystic Fibrosis Center at the University of North Carolina, and is expected to uncover the mechanisms involved in both healthy and diseased airway clearance.

ABSTRACT

Proposal No.: 0609087

Title: NIRT: Engineered Molecular Fluidics

PI: Sheiko, Sergei S.

Institution: University of North Carolina at Chapel Hill

This proposal was received in response to Nanoscale Science and Engineering initiative, NSF 05-610, category NIRT. This project will explore a new direction in micro-fabricated fluidics molecular fluidics wherein one can monitor, probe, and manipulate flows one molecule at a time. Investigations will be performed on the behavior of fluid mono-layers residing on solid substrates that can be manipulated by both electric fields and intrinsic means such as the interaction with the substrate. The proposed approach is based on synthetic design of flow- and electric field-responsive molecules, experimental and theoretical studies of surface-confined macromolecules under flow, and the engineering of flow actuation techniques. The flow will be monitored over a broad range of length scales from the motion of the film front all the way down to the movements of individual molecules within the film. Since molecular conformation responds to flow and may respond to external stimuli such as electric fields, one anticipates the development of molecular devices that can both probe the flow properties and actively affect the flow structure. If successfully implemented, electrically controlled surfaces will lead to creation of a new range of materials and devices that enable anisotropic wetting, directional liquid transport, and anisotropic tribology, and may even be self-cleaning or direct the growth of live cells for biomaterials and implants. Experimental findings will be continuously tested against theoretical predictions and computer simulation studies, and will guide the synthesis of additional functional macromolecules.

With respect to broader impacts, the proposed research will advance fundamental understanding of the conformation and dynamics of surface-confined polymer chains and lead to the development of new theories for interfacial flow and its interaction with electric fields. Furthermore, the highly interactive and efficient teamwork in the proposed multi-disciplinary research area will ensure maximum opportunity for integrating science and education based on the interdisciplinary training of student and postdocs, partnerships with 6-12 schools, and involvement of underrepresented groups. The collaborative education plan involves three areas of activity: (i) the development of a new graduate course and a new lab module, (ii) co-advising and an exchange of students that will experience a highly interdisciplinary education in polymer chemistry, advanced polymer theory, visualization and micro-fabrication techniques, (iii) and regular interactions with local high schools in form of introductory lectures and summer research programs at our universities. One of the most important goals is to bring molecular visualization from university to high-school classrooms where the ability to see molecules would be invaluable for the teaching of molecular structures and chemical reactions.

The PI and his research team are proposing a major new project to develop theory and organize methods for understanding and computing with L-functions and modular forms. Broadly speaking, they plan to chart the landscape of L-functions and modular forms in a systematic and concrete fashion. They will study these functions, develop algorithms for their computation, and test fundamental conjectures, including: the Generalized Riemann Hypothesis, the Birch and Swinnerton-Dyer conjecture, the Bloch-Kato conjecture, the correlation conjectures of Montgomery and of Rudnick-Sarnak, the density conjectures of Katz-Sarnak, automorphy of the Hasse-Weil zeta functions, and the Selberg eigenvalue conjecture. They plan to carry out a systematic study, theoretically, algorithmically, and experimentally of degree 1, 2, 3, 4 L-functions and their associated modular forms, including classical modular forms, Maass forms for GL(2), GL(3), GL(4), Siegel modular forms, and Hilbert modular forms. They will also investigate symmetric square and cube L-functions, Rankin-Selberg convolution L-functions, the Hasse-Weil L-functions of algebraic varieties, Artin L-functions associated to 3- and 4-dimensional Galois representations, and, less systematically, look at a few high degree L-functions associated to higher symmetric powers and higher dimensional Galois representations.

L-functions and modular forms underlie much of twentieth century number theory and are connected to the practical applications of number theory in cryptography. Virtually all branches of number theory have been touched by L-functions and modular forms. Besides containing deep information concerning the distribution of prime numbers and the structure of elliptic curves, they feature prominently in Andrew Wiles' solution of the famous 350-year-old Fermat's Last Theorem, and in the twentieth century classification of congruent numbers, a problem first posed by Arab mathematicians one thousand years. In spite of their central importance, mathematicians have only scratched the surface of these crucial and powerful functions. The PI and his research team are undertaking a major new project to systematically tabulate and study these functions. Their work will fall into four categories: theoretical, algorithmic, experimental, and data gathering. The theoretical work will be stimulated by their goal of charting the world of L-functions and modular forms. Their experimental work will involve testing many key conjectures concerning these functions. The project will produce a large amount of training, with plans for three graduate student schools, an undergraduate research experience, and support for a score of postdocs and graduate students who will assist in research. It will result in the creation of a vast amount of data about a wide range of modular forms and L-functions, which will far surpass in range and depth anything computed before in this area. The data will be organized in a freely available online data archive, along with the actual programs that were used to generate these tables. By providing these tables and tools online, the researchers will guarantee that the usefulness of this project will extend far beyond the circle of researchers on this FRG. The archive will be a rich source of examples and tools for researchers working on L-functions and modular forms for years to come, and will allow for future updates and expansion.

This award will provide computational equipment (servers) which would support research by three related groups of researchers into the frontiers of Representation Theory, Number Theory, and Mathematical Physics.


The Representation Theory group will compute the Kazhdan-Lusztig-Vogan polynomials for all simple Lie groups up to rank 9 and make the results of these computations readily available to researchers worldwide. This group will also continue to explore the combinatorial infrastructure of W-graphs and relate it to representation theoretical invariants.


The Number Theory group will carry out major computations of modular forms and Lfunctions, and greatly enhance our understanding of the Birch and Swinnerton-Dyer conjecture and the Riemann Hypothesis, two of the central problems in number theory.


The Mathematical Physics group will complete the first major step in the classification of off-shell representations of Supersymmetry, a problem that has been open for three decades.

Abstract


Principal Investigator: Rubenstein, Michael
Proposal Number: DMS - 0753794
Institution: American Institute of Mathematics
Title: Canadian Number Theory Association X Meeting


The Canadian Number Theory Association (CNTA) was founded in 1987 at the
International Number Theory Conference at Laval University. The purpose
of the CNTA is to enhance and promote learning and research in Number Theory.
To advance these goals, the CNTA organizes major international conferences,
with the aim of exposing students and researchers to the latest developments
in number theory. The previous meetings have been held in Banff (1988),
Vancouver (1989), Kingston (1991), Halifax (1994), Ottawa (1996), Winnipeg (1999), Montreal (2002), Toronto (2004), and Vancouver (2006). The tenth meeting of the CNTA is scheduled to take place on the dates July 13-18, 2008 at the University of Waterloo. The direct impact of NSF funding will be the training of a significant number of junior US researchers (junior faculty, postdoctoral fellows and graduate students), who will gain the opportunity to participate in the workshop. Almost half of those who attended CNTA IX (Vancouver 2006) were American (95 people); the rest were from Canada (57), Europe (32), Asia (13), Africa (3), Australia (3), and Latin America (2).

The conference will contain 12 plenary lectures, including a talk given by the
winner of the 2008 Ribenboim Prize (an award for distinguished research in number theory), and a lecture open to the general public. The conference will also include more than one hundred lectures in several special sessions, covering areas in algebraic number theory, analytic number theory, arithmetic geometry, computational number theory, and diophantine analysis. These topics form the core of number theory, a vast subject with origins in classic greek mathematics and having important applications in a wide range of areas including cryptography, graph theory, coding theory, combinatorics, and logic, to name just a few.

Michael Rubinstein of the University of North Carolina, Chapel Hill, is supported by an award from the Theoretical and Computational Chemistry program to develop a theory of the self-healing process for the major class of autonomic self-healing polymeric material: networks with reversible associations and dissociations. The self-healing ability of these polymers originates in high non-equilibrium concentration of dissociated groups created at the fractured surfaces that decays very slowly during a "waiting" time while two broken parts of the material are kept separated from each other. One of the objectives of the project is to determine which molecular parameters, such as degree of polymerization, number of associating groups per chain, and the strength of associations maintain the high excess of dissociated groups at the fractured surfaces for the longest period of waiting time.

The research contributes to the development of synthetic self-healing materials which are expected to have major technological impact by extending the working life and safety of polymeric components used in a broad range of applications. Results of this research are incorporated into new problem sets and supplementary materials for the "Polymer Physics" textbook by M. Rubinstein and R. H. Colby. Examples of self-healing materials are being used in the design of the updated "Zoom In" exhibit at the Morehead Planetarium and Science Center as well as in lectures by the PI to high school students at the "Science Spectrum" and "Science at the Edge" series at UNC.

TECHNICAL SUMMARY
This award supports theoretical research and education in the area of polymer networks and entangled gels. The elastic properties of polymer networks and gels, used in a wide range of applications from hard rubber boots to soft gel replacements for eye lenses, are determined by chemical cross-links as well as by topological entanglements between network strands. Existing theories of gels treat entanglements in qualitatively the same way as crosslinks. However, experiments suggest that their relative role changes upon network swelling and deformation. Thus a microscopic theory is needed that provides a qualitative explanation of this phenomenon as well as a quantitative description of macroscopic properties of deformed and swollen entangled gels.

The PI aims to develop a theory that will allow the calculation of the elastic modulus and equilibrium swelling of entangled gels along with stress-strain dependence for their uniaxial and biaxial deformations. The theory will be extended to explore novel networks with unique properties such as high deformability and low elastic modulus. The effect of trapped entanglements in swollen and deswollen gels will be modeled, emphasizing their qualitative difference from temporary entanglements in polymeric liquids. The dependence of topological interactions on network deformations will be calculated, and used to understand why the strength of these interactions becomes weaker in elongation directions and stronger in compression directions. New numerical methods will be developed to determine the dependence of entanglement parameters, such as confining tube diameter and persistence length, on deformation of polymeric systems with fixed topology. These methods will be used to test the assumptions and predictions of different theories of entangled networks.

This project will provide graduate students and postdoctoral fellows with an excellent opportunity for training in valuable analytical and numerical techniques. Some of the results of this research will be used to develop material for a textbook. The proposed project will stimulate the interest of high school students in modern scientific methods by engaging them in active research. Examples of elastic gels will be used in the design of the updated "Zoom In" exhibit at the Morehead Planetarium and Science Center as well as in lectures by PI to high school students at the "Science Spectrum" and "Science at the Edge" series.

NONTECHNICAL SUMMARY
This award supports theoretical research and education on networks of long chain-like molecules, including interpenetrating chains that are swollen by a solvent, like water. The unique interplay of solid-like properties on large length scales and liquid-like properties on small length scales makes these polymer networks and gels the world?s most deformable elastic materials. Their elastic properties, used in a wide range of applications from hard rubber boots to soft gel replacements for eye lenses, are determined by chemical interactions between the chain-molecules as well as by entanglements among chain-molecules in the network. Most theories for the elastic and mechanical properties of these kinds of materials treat the effects of entanglements in polymer networks qualitatively the same way as chemical bonds creating hard links between polymer strands. Experiments suggest, however, that the relative role of the two physical effects changes upon network swelling and deformation caused by external conditions. The PI aims to fill the need for a microscopic theory that can explain this phenomenon and describe the properties of these materials.

The theory has the potential to uncover new routes for designing soft materials with a desired set of properties. The project will provide undergraduate and graduate students as well as postdoctoral fellows with an excellent opportunity of training in valuable analytical and numerical techniques. Some of the results of this research will be used in the developing materials for a textbook. The proposed project will stimulate the interest of high school students in modern scientific methods by engaging them in active research. Examples of elastic gels will be used in the design of the updated "Zoom In" exhibit at the Morehead Planetarium and Science Center as well as in lectures by PI to high school students at the "Science Spectrum" and "Science at the Edge" series.

DESCRIPTION (provided by applicant): The goal of this proposal is to develop physical understanding of and therapies for the failure of mucus clearance in patients with chronic bronchitic (CB) diseases, where mucus becomes sticky and adheres to the epithelial cell surface periciliary layer (PCL). We hypothesize that a unifying feature of CB diseases is dehydration of mucus that reflects common elements of pathogenesis in both genetic (e.g., cystic fibrosis) and environmental (e.g., cigarette smoke-induced) forms of CB. We hypothesize that the failure of CB mucus clearance is due to the higher adhesion and cohesion strengths between CB mucus and PCL that reflects mucus dehydration. In Sp. Aim 1, we will develop experiments, such as peel tests and cavitation rheology technique (CRT) in cultured cell preparations, which would allow us for the first time to measure the adhesion strength between mucus and PCL, the cohesion strength of mucus at different mucus concentrations, and crack propagation rates. Both the adhesion and cohesion strength will be quantified systematically and related to the viscoelastic properties of mucus in corresponding conditions. In Sp. Aim 2, we will measure mucus adhesion and cohesion in freshly excised ainways from human subjects with cigarette smoke-induced CB and CF, and compare data with cell culture model data. We will also test the relevance of a mouse model of airways mucus adhesion, the pENaC transgenic mouse, to human diseases. In Sp. Aim 3, we will test combinations of hydrating and mucolytic agents for therapeutic activity in CB subjects. This Aim will progress single agents/combinations from in vitro testing in cultured cells, using peel test and CRT measurements, to combination therapies in acute and 2 week in vivo testing in the (3ENaC mouse model. The overall goal of the project is to have a novel combination therapy identified for clinical testing in CB subjects within 2 years. RELEVANCE (See Instructions): Chronic bronchitis (CB) is caused by both genetic and environmental factors and affects more than 14 million Americans. Currently, there is little knowledge about the mechanism/or treatment ofthe abnormal airway sections that adhere to ainway surfaces in CB. We propose to utilize novel concepts from polymer physics and methodologies from material sciences to develop much needed effective therapies for CB.

Patients with cystic fibrosis (CF) and chronic bronchitis, i.e. COPD, exhibit a significantly reduced mucus clearance. The overarching goal of this project is to test the hypothesis that reduced rates of mucociliary and cough clearance in these patients are related to mucus dehydration and the resulting increased adhesion of mucus to cells as well as increased mucus cohesion strength. Both CF and COPD subjects exhibit an increase in ainvay mucus concentration, reflecting: 1) reduced ainway surface solvent (salt/water), e.g., as observed with CFTR dysfunction; 2) mucin hypersecretion, as observed with goblet cell hyperplasia; or 3) a combination of the two. Based on our recent theoretical and experimental data, we have developed a novel model, referred to as the two-gel model, that suggests that in addition to a mucus gel, ain/vays exhibit a periciliary layer (PCL), which is also a gel formed by tethered mucins (MUC1, MUC4, and MUC16). Efficient clearance requires hydration of the PCL that is sustained as long as its osmotic pressure is higher than that of the mucus gel layer. Importantly, the osmotic pressure of the mucus layer is largely determined by the concentration of the secreted mucins MUC5AC and MUC5B. To test our two-gel hypothesis, we have developed novel techniques to measure mucus osmotic pressure, adhesion/cohesion strength, viscosity, and elastic modulus and to determine the effect of these physical properties on mucus transport rate for both normal and CF cultures. We propose that reducing mucus concentration, cohesion strength, and mucus adhesion to epithelial cells will restore effective mucus clearance and thus benefit both CF and COPD patients. The novel approach to physical processes in airway surface layer will allow us to identify the optimal combination of rehydration and pharmacological agents to restore/accelerate the rate of mucus clearance. The identified agents that reduce the adhesion/cohesion strength and restore normal mucus clearance will be tested in mouse models of obstructive lung disease (Project II) and in COPD patients (Projects III). RELEVANCE (See instructions): This project focus on the developments and validation of new physical models of airway surface layer and the role of mucus hydration, adhesion and cohesion in controlling mucus clearance. These new ideas lead to systematic developments of new drugs aimed at restoring and maintaining mucus clearance in patients with obstructive lung diseases.

TECHNICAL SUMMARY

This award supports theoretical and computational research on the motion of nanoparticles in a polymer matrix. The mean square displacement of microscopic particles larger than polymer chains provides information about rheological properties of the surrounding matrix. However, structure and dynamics of complex polymeric materials on sub-molecular length scales as well as microscopic details of polymer-particle interactions are poorly understood. The PI will analyze the motion of nanoparticles smaller than the surrounding polymer chains. Particularly interesting is the coupling of the nanoparticle dynamics to dynamical modes of matrix polymer chains on length scales equal to or smaller than the particle size and to modes of chains adsorbed or grafted to the particle.

A theory of the dynamical coupling between nanoparticles and a polymer matrix will be systematically developed starting from a model of non-sticky particles freely diffusing in polymer networks and gels. Mobility of these trace particles is highly sensitive to the relation between their dimensions and the diameter of the confining tube of the entangled matrix chains. Upon uniaxial and biaxial deformation of polymer networks and gels, the corresponding change of the tube diameter causes anisotropic diffusion of tracer nanoparticles. A method for characterization of the non-affine deformation of the confining tube by measuring the anisotropy of nanoparticle mobility will be developed and tested by computer simulations. The developed models will also enable quantitative analysis of translational and rotational diffusion of non-spherical nanoparticles, such as nanorods with diameter smaller than the mesh size of polymer gels and length longer than this mesh size.

The model will be extended to the case of sticky nanoparticles that exhibit hindered diffusion through polymeric liquids or solids due to chains attached to these particles. The time dependence of the mean square displacement of the sticky particles will reflect both dynamics of attached chains as well as of the surrounding polymer matrix. The proposed theory will allow separation of both contributions and determination of the structure and dynamics of the polymer layer adsorbed on nanoparticles. This theory will be modified to treat the finite lifetime of the bonds between particles and adsorbed polymers and the lifetime of labile bonds in reversible networks.

The theory of mobility of sticky particles will be extended to treat heterogeneous medium with a distribution of local sticky regions using an activated hopping model. A general solution of this model will be obtained to allow the derivation of the distribution of attraction strengths of different sticky regions from the analysis of particle trajectories.

This project will provide training opportunities for undergraduate and graduate students as well as postdoctoral fellows in analytical and numerical techniques for soft materials. Some of the results of this research will be used in the development of new problem sets and supplementary materials for the PIs textbook "Polymer Physics." The project will also be used as a tool for engage the interest of high school students in modern scientific methods by engaging them in active research.

NONTECHNICAL SUMMARY

This award supports theoretical and computational research to study nanoparticles, particles some 100,000 times smaller than the diameter of a human hair, moving within a material made up of a tangle of long chain-like molecules called polymers. Understanding the mechanisms by which the nanoparticles move provides useful information about the properties of materials made of polymers. The PI will develop a theory that can handle nanoparticles of different sized and shape, as well as kind, including nanoparticles with smooth surfaces and nanoparticles that have polymers attached to them which tend to make them "sticky" as they interact with the polymers that make up the material. This research will has impact on technological applications, such as optimizing composite materials and designing nanoparticles for drug delivery applications.

This project will provide training opportunities for undergraduate and graduate students as well as postdoctoral fellows in analytical and numerical techniques for soft materials. Some of the results of this research will be used in the development of new problem sets and supplementary materials for the PI's textbook "Polymer Physics." The project will also be used as a tool for engage the interest of high school students in modern scientific methods by engaging them in active research.

NON-TECHNICAL SUMMARY
Many studies have focused on developing materials for conventional acoustic applications, such as ultrasound imaging, sound insulation, and geological logging. However, the design of materials that actively respond to sound and concurrently shift their acoustic and optical characteristics remains in its infancy. The goal of this project is to design acoustically responsive materials that alter their chemical structure, physical properties, and object shapes whenever they interact with sound waves enabling active modulation of acoustic properties including speed of sound, attenuation, and phononic band gaps. If compared to electromagnetic radiation, sound waves possess unique physical characteristics as they readily propagate through optically non-transparent materials, including liquids, solids, and gels (e.g., human body), where direct application of conventional stimuli, such as light and electric fields, is either physically or physiologically prohibited. This enables non-invasive interrogation of a wide range of materials properties and remote activation of various mechanochemical processes. Moreover, similar to electromagnetic radiation, sound can be focused both in space and in time. This opens intriguing opportunities to perform local modifications in a time-controlled, sequential manner. These materials may be utilized both in materials engineering for acoustic lithography and self-healing and in biomedical applications including non-invasive surgery, diagnostics, and drug-delivery.


TECHNICAL SUMMARY
The project goal is to develop a new direction in materials design wherein fundamental changes in materials properties are activated by sound waves that concurrently shift acoustic, optical, and geometric characteristics of macroscopic objects. The research activities pursue three strategic objectives. First, develop fundamental understanding of hierarchic correlations between the multi-scale architecture of complex macromolecules and mechanical properties of materials assembled of these molecular mesoblocks. Theoretical studies will provide guidelines for synthesis of materials with an extraordinarily broad range of elasticity, strength, and toughness that are currently not available in conventional polymer systems. Second, study the interaction of sound waves with stimuli responsive polymer systems and explore different activation mechanisms that shift density, modulus, compressibility, and shape. Understanding the feedback between acoustically triggered changes in materials properties and the corresponding shifts in acoustic characteristics represents an intellectual challenge of this proposal. Third, create a novel class of materials that can be activated, actuated, and navigated remotely using acoustic fields in a programmable and time-resolved manner. An anticipated culmination of this project is acoustically transformative materials that not only respond to sound but also fundamentally change their physical properties, object dimensions, and acoustic and optical characteristics. The collaborative nature of this project will ensure interdisciplinary training of junior researchers in polymer synthesis, physical experiments, and theory. The project also provides opportunity for broadening participation of underrepresented groups and fostering infrastructure for collaborative research.

Patients with muco-obstructive lung diseases (CF, COPD, and asthma) suffer from reduced mucus clearability due to accumulation of sticky, adherent, mucus in their airways. In order to understand the pathogenesis of these diseases, it is necessary to understand both the mechanisms that mediate efficient mucus clearance in health and how alterations in this system leads to failed mucus clearance in each of these disorders. Our overarching hypothesis is that reduced mucus clearance in disease is a result of multiple alterations in the composition and physical properties of the airway mucus. Based on our preliminary data, such changes in mucus properties come as a result of: 1) disease-related increases in mucus concentration, 2) alteration in the ratio of MUC5AC (the dominant asthma mucin) vs. MUC5B (the dominant CF/COPD mucin), and/or 3) oxidation of mucins resulting in additional cross-links. We hypothesize that such alterations in the mucus layer will produce a more ?sticky? (more viscous, adherent, tear-resistant) mucus that will be harder to be cleared by the action of cilia beating and coughing. There is currently a lack of knowledge of how such changes in the mucus alter the biophysics properties of the mucus and how such changes lead to reduced mucus clearance. To answer these questions, studies in Aim 1 are designed to test the effect of altering mucus concentration and MUC5AC:MUC5B ratio on mucus biophysical properties (rheology, adhesion and cohesion strength, and friction) and how such alterations affect the rate of mucus clearance by cough and cilia beating. Once it has been established how disease alters mucus clearance, our goal, in support of the tPPG clinical projects 3 & 4 is to determine how best to restore mucus clearance in patients with mucus obstructions. We hypothesize that there are two separate, but complementary, approaches to clear adherent mucus from the airways. The simplest is to reduce the mucus concentration, via hydration. The second is by breaking down the structure of mucus through reduction in mucin molecular weight using reducing agents. Importantly, we hypothesize that such approaches may be additive/synergistic. In Aim 2 we will test these hypotheses by correlating reducing agent-mediated changes in mucin molecular weight/size combined with hydration-mediated changes in mucus concentration on changes in mucus biophysical properties and assess the impact of these changes on stimulating both cilia- and cough-mediated mucus clearance. In Aim 3, we will assess the role of inflammation- mediated oxidation of mucus in the formation of a permeant, non-swellable, mucus gel, which can severely limit clearance from the airways. We will test the hypothesis that hydration method alone is not sufficient, but a combination of hydrator plus a reducing agent is required to restore the mucus clearance. Overall, the studies in Project 1 are expected to support other tPPG Projects by advancing our understanding of the mechanism(s) of defective mucus clearance in disease and identifying the most effective therapeutic combination of hydrating and reducing agents to maximally restore mucus clearance in patients with CF, COPD, and asthma.

The structure of the human genome inside of a living cell is precisely and dynamically controlled to determine the level of each gene in different cell types, in response to environmental stimuli, and in various disease conditions. The chemical modification and three-dimensional folding of our DNA plays an even greater role than our inherited genetics in human development, disease progression, and drug response. There have been tremendous advances in mapping genome sequence and structure but our understanding of the relationship between genome structure and function is relatively poor. The objective of this proposal is to cross interdisciplinary boundaries to develop the necessary technologies to accurately predict, quantitatively monitor, and deterministically program genome structure to generate improved disease models that will catalyze transformative drug development. The team will also develop educational programs to inspire the next generation of scientists in this emerging discipline.

Innovative new technologies, including reporters of dynamic molecular structure and CRISPR/Cas9-based epigenome editing, provide a unique opportunity to monitor and perturb epigenetic states that govern chromatin structure. The team will generate new molecular tools for monitoring changes to epigenetic states in live cells using FRET-based nanosensors that report on structural changes to chromatin structure and mechanics in response to targeted perturbations by CRISPR/Cas9-based epigenome editing. This data will inform molecular models that predict the effect of epigenetic changes on chromatin structure and consequent changes in gene expression. These technologies and models will be validated in the context of human tumor models to illuminate the relationship between chromatin structure and cancer progression. Collectively, this will enable the development of new technologies and models that are broadly useful for disease modeling and drug screening.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.