2003 — 2007 |
Goodson, Holly V |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Interactions Between Clip-170 and Tubulin @ University of Notre Dame
DESCRIPTION (provided by applicant): The process of cell organization underlies fundamental biological processes ranging from polarized growth to multicellular development. The long-term goal of the Goodson laboratory is to understand the origins of this organization. Because many aspects of cell organization depend on the microtubule cytoskeleton, a major part of this initally diffuse problem can be reduced to two questions:: a) How is the microtubule cytoskeleton itself morphologically defined? b) How do other cellular components interact with microtubules? To answer these questions requires knowledge of the proteins that control microtubule (MT) dynamics and mediate cargo-MT interactions. This proposal focuses on CLIP-170, an evolutionarily conserved MT-binding protein that is involved in both processes. CLIP-170 also has the intriguing property of localizing dynamically to growing MT plus ends. The goal of this proposal is to define interactions between CLIP-170 and MTs how CLIP-170 associates with MTs, the mechanism and significance of its dynamic plus-end tracking behavior, and the precise effects it has on MT dynamics. This knowledge will establish CLIP-170 function and mechanism, aid in understanding other MT plus-end tracking proteins, and help define the regulation of MT growth. Our Specific Aims are to: 1. Determine the affinity of CLIP-170 for different conformational states of tubulin/MTs by biophysical techniques including MT cosedimentation, fluorescence anisotropy, and surface plasmon resonance. This work will establish which interactions are physiologically relevant and test plus-end tracking mechanisms. 2. Define the effect of CLIP-170 on MT dynamics by performing in vitro MT dynamic instability assays in purified systems and in Xenopus extracts. This will define CLIP-170 activity and establish a system for further study of CLIP-170 regulation and protein partners. 3. Define the minimal plus-end tracking domain by transiently transfecting tagged CLIP-170 fragments into tissue culture cells and assaying their ability to track MT plus ends in vivo. This will allow us to establish the relationships between CLIP-170 structure, plus end tracking activity, and effects on MT dynamics, and will provide a simplified system for dissecting regulation involved in plus end tracking behavior.
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1 |
2010 — 2014 |
Alber, Mark (co-PI) [⬀] Goodson, Holly |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Computational and Experimental Studies of Microtubule Dynamics and Regulation by Binding Proteins @ University of Notre Dame
Intellectual merit. Microtubules (MTs) are the primary components of crucial subcellular structures including the intracellular transport network and the mitotic spindle that separates the chromosomes during cell division. A central problem in cell biology is to understand how these MT-based structures form, are dynamically maintained, and drive the organization of the rest of the cell. Classically, these questions have been addressed by identifying and characterizing the proteins that regulate MT dynamics. While this approach has been powerful, it is not sufficient: the MT cytoskeleton is a complex system that exhibits behaviors ("emergent properties") not straightforwardly predictable from analysis of the individual components. Such a system level problem requires system level approaches: mathematical and computational modeling. The goals of this project are to develop, utilize, and experimentally test two computational models of MT dynamics, and to use these models to investigate the function and mechanism of MT binding proteins. These models will be built at two scales: a mesoscopic (medium scale) model that will be used to investigate the intrinsic properties of a system of dynamic MTs in a cell-like environment, and a molecular scale model that will be used to develop hypotheses about the mechanisms of dynamic instability and its alteration by MT binding proteins. The long-term goal of this work is to develop a predictive and quantitative understanding of the MT cytoskeleton and its regulation by MT binding proteins, which will impact fields ranging from systems biology to nanotechnology. Broader impacts. An important part of this project is to develop a freely disseminated software suite "MT Toolbox" (MTT), which will include analysis tools and instructional electronic tutorials. MTT will have two implementations: 1) a web-based interface that will allow scientists and students at remote sites to submit jobs for running the models and their analysis tools on our server; 2) a freely disseminated software suite containing all programs with online tutorials, user, and programmer's guides. The flexible models and tutorials produced through this project will allow researchers to develop and test specific hypotheses about the mechanisms of MT dynamics, which will in turn help design and direct future experiments. More broadly, it will help students and researchers at all levels gain an intuitive understanding of dynamic MT systems. The project will educate three graduate students and two undergraduates who will benefit from interdisciplinary training in biology and computational modeling. Projects related to the proposed research will be incorporated in The Research Experience for Teachers at Notre Dame (RET@ND) program as well as the Notre Dame McNair Program, which promotes graduate and doctoral studies for minority students.
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0.915 |
2012 — 2015 |
Turkewitz, Aaron Lynch, Michael Goodson, Holly |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Workshop: Evolutionary Cell Biology, May 29-31, 2012, Warrenton, Virginia @ University of Notre Dame
Intellectual Merit The Evolutionary Cell Biology Workshop will be held at the Airlie Conference Center in Warrenton, Virginia. The goal of this multi-investigator project is to organize a Workshop that will bring together investigators from diverse scientific communities and with diverse perspectives including evolutionary biologists, cell biologists and computational biologists to define the nascent field of "evolutionary cell biology" and to identify the key issues and fundamental principles that are in most urgent need to being addressed in order to foster this exciting and emerging area of research. With the fact that there are mature fields of molecular evolution, genome evolution and even developmental evolution, there is no recognizable field of evolutionary cell biology. With that in mind, this is an opportunity for both cell biologists and evolutionary biologists alike. Therefore, the potential payoff of organizing a meeting that focuses on evolutionary biologists and cell biologists is significant. The development of a field of evolutionary cell biology should have impacts on disciplines beyond cell and evolutionary biology, e.g., by helping scientists figure out how to rationally alter cell biological features or even to invent new ones, thereby contributing to the emerging fields of synthetic biology and artificial life.
Broader Impacts The development of a field of evolutionary cell biology is expected to have major impacts on the disciplines of cell biology and evolutionary biology but it will influence other fields as well. Establishing an understanding of the principles of evolutionary cell biology should help scientists establish how to rationally alter cell biological features or even to invent new ones, thereby contributing to the emerging fields of synthetic biology and artificial life. The requested funding will be used to support travel, meals and/or lodging for 35 participants from US and international locations.
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0.915 |
2013 — 2017 |
Alber, Mark (co-PI) [⬀] Goodson, Holly |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Biomaps: Experimental and Computational Studies of Microtubule Dynamics and Regulation by Binding Proteins @ University of Notre Dame
INTELLECTUAL MERIT The goal of this project is to use coordinated experiment and computational modeling to answer fundamental questions about the system-level behavior of the microtubule cytoskeleton. Microtubules (MTs) are the primary components of crucial subcellular structures including the mitotic spindle, which segregates the chromosomes, and the intracellular transport network, which organizes the cytoplasm. Understanding how MT-based structures assemble, are maintained, and drive cell organization is a central problem in cell biology. MTs exhibit a surprising behavior known as dynamic instability -- individual MT fibers transition randomly between extended phases of growth and depolymerization. The long-term goal of this project is to establish an understanding of DI and its regulation by MT binding proteins by coupling experiment with iterative multi-scale modeling. The specific goals of this research are: 1) Obtain an understanding of, and seek to establish, a set of general principles for how MT binding proteins cooperate to modulate MT dynamics and polymer mass using MT plus-end tracking proteins as a model; 2) Define the relationship between the behavior of the bulk MT polymer and that of individual MTs. A key goal is to use modeling approaches to investigate and refine classical theories of equilibrium polymers that define MT dynamics. While the focus is on MTs, the improved understanding should be relevant to other cytoskeletal polymers; 3) Develop freely disseminated software packages with associated tools and instructional electronic tutorials to help students and researchers gain an intuitive understanding of dynamic MT systems using computational models of MT assembly.
BROADER IMPACTS This projects combined modeling and experimental effort will help students and researchers at all levels gain an intuitive understanding of dynamic MT systems. This understanding is important for applications ranging from nanotechnology (the mitotic spindle is a striking example of a self-organized nanotechnological system) to controlling agricultural pests (some prominent antiparasitic and antifungal compounds are directed at MTs). The PIs will integrate the software tools developed as part of this project into their classes. The project will also educate graduate and undergraduate students who will benefit from interdisciplinary training in biology and computational modeling. Projects related to this research will be incorporated in The Research Experience for Teachers at Notre Dame program as well as into programs promoting graduate and doctoral studies for minority students.
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0.915 |
2016 — 2019 |
Tank, Jennifer (co-PI) [⬀] Goodson, Holly |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Idbr: Type a: Development of a Yeast-Based Continuous Culture System For Detecting Bioavailable Phosphate @ University of Notre Dame
An award is made to The University of Notre Dame to develop a remotely deployable yeast based biosensor that measures the amount of bioavailable phosphate in water. Eutrophication, pollution of surface water supplies through excess nutrients, can result in harmful algal blooms and the degradation of the quality of surface waters throughout the globe. Thus, the Broader Impacts of the project include helping to reduce the over abundance of nutrients in water supplies, protecting the environment, drinking water, and property values, and optimizing fertilizer use (reducing farming costs and conserving the limited resource phosphate). The education and outreach efforts will include development of a simplified batch-culture-based assay for use in schools and community settings, which will broaden environmental participation and awareness of the need to reduce phosphate waste. In addition, the analytical chemistry and ecology students involved in the project will each receive cross-disciplinary training in the other field.
Improving the technology for measuring phosphate is important because eutrophication (pollution through excess nutrients) is degrading the quality of surface waters throughout the globe, and monitoring of phosphate is largely still limited to laborious lab-based, wet chemistry approaches. The goal of the project is to address this problem by developing a biologically-based phosphate sensor that is continuous, relatively inexpensive, remotely deployable, able to test turbid water, and based on monitoring the growth of the yeast Saccharomyces cerevisiae. The principle behind the device is that all organisms (including yeast) need phosphate to grow; yeast are ideal organisms for this work for reasons including their robustness to environmental perturbation and resistance to water-borne viruses. Since yeast growth is linear with phosphate concentration in the relevant phosphate concentration range, changes in the amount of bioavailable phosphate in water will be measured by monitoring the growth and respiration of yeast in this continuous culture system under conditions where the test water is the only source of phosphate. Because this sensor will measure bioavailable phosphate, not simply dissolved reactive phosphate (DRP) or total phosphorous (TP) as measured by other standard approaches, it will represent an important new tool for any environmental or engineering studies involving freshwater and should provide insight into previously inaccessible aspects of nutrient dynamics in aquatic systems.
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0.915 |
2018 — 2022 |
Goodson, Holly |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Collaborative Research: Developing a Multi-Scale Understanding of Microtubule Dynamic Instability @ University of Notre Dame
Most cells in a wide range of organisms contain a dynamic substructure called the cytoskeleton, a network of protein-based polymers and associated proteins that has fundamental roles in cell movement, DNA partitioning, and internal cell organization. A key aspect of many cytoskeletal polymers is that they require chemical energy in the form of ATP (or GTP) to maintain a polymerized state. The harnessing of this energy allows the cytoskeletal filaments to do work, respond dynamically to internal and external signals, and self-organize. The major goal of the work in this project is to use a combination of experiments and computational modeling to develop an improved theoretical framework for understanding and predicting the behaviors of these dynamic cytoskeletal polymers as observed at different scales. More specifically, the proposed work sets out to establish how the biochemical properties of the polymer subunits (including the rate at which they burn ATP or GTP) relate to the behaviors of the individual filaments and to the overall behaviors of populations of filaments. In addition, the project studies how filament binding proteins work together to regulate filament dynamics. While this work is basic science, it has the potential to have practical applications in nanotechnology and synthetic biology. Through this project, graduate students and undergraduates will receive interdisciplinary training in both computational modeling and experimental biology. High school teachers and students will also be engaged in the research process. Freely available, open-source software and tutorials produced through this project will help students and researchers at all levels gain an intuitive understanding of dynamic polymer systems.
From a technical perspective, the project has four specific goals, most of which focus on a type of cytoskeletal filaments known as microtubules. Individual microtubules exhibit a dramatic behavior known as dynamic instability, in which they stochastically alternate between extended periods of growth and depolymerization. (1) The first project goal is to develop and test hypotheses for the mechanisms of the transitions in microtubule dynamic instability by relating the behaviors of the filaments to the subunit-level structure of their tips. The approach will utilize a combination of work with a previously established detailed computational model of microtubule dynamics, a novel data analysis tool for identifying and statistically categorizing the microtubule behaviors, and experimental data acquired at high temporal and spatial resolutions. (2) The second goal is to establish a predictive understanding of the relationships between the biochemical characteristics of the subunits (kinetic rate constants), the behaviors of the filaments (e.g., dynamic instability, treadmilling) and the attributes of the polymer systems (e.g., critical concentrations, steady states). The approach will utilize a combination of computational modeling (performed with variants of the model used in Goal 1) and experiments with a bacterial relative of tubulin called PhuZ (chosen because wildtype and altered versions of this protein can be expressed in bacteria and characterized in vitro). (3) The third goal is to use a combination of experiments and computational models to test a set of hypotheses for how a group of filament binding proteins known as +TIPs (microtubule plus-end tracking proteins) work together to regulate microtubule behavior. (4) The final goal is to create for broad distribution packages of our software and associated analysis tools used in Goals 1 to 3. These packages will include software targeted at both the research and teaching communities. While the focus of our studies is on microtubules, the resulting multi-scale understanding of polymerizing filament systems should apply to steady-state (energy-utilizing) polymers more generally, including actin, bacterial filaments, and polymers created through biotechnology.
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.
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0.915 |
2020 — 2023 |
Goodson, Holly |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Transitions: Experimental Evolutionary Cell Biology @ University of Notre Dame
Evolutionary cell biology is an emerging field that has the potential to provide insight into the myriad ways cells work along with the evolutionary processes and constraints which molds their structures and functions. The goal of this project is to help provide valuable training to a cell biology group, which will enable them to tackle important problems in this emerging field. Specifically, the group will gain expertise in growing cells of an ecologically important red algae, but one in which cell biology understanding is limited. In an interdisciplinary collaboration, insight will be gained into how these algae have evolved without the benefit of what is typically considered to be essential proteins. The PI and the collaborating group will use the resulting broad perspectives and interdisciplinary tools to identify proteins and mechanisms that are common across divergent cellular organisms, helping to illuminate basic cell biological and evolutionary processes. Broader Impact activities will include the training of high school students, undergraduate and graduate students in research methods and additional outreach work will target an older generation on the interrelatedness of science.
This research consists of two projects. Project 1 has two goals: a) to experimentally test hypotheses developed from phylogenetic analysis of how the red alga Porphyra umbilicalis accomplishes core biological processes (e.g., cell movement, membrane transport, cell division) without key cytoskeletal proteins; b) to deepen our understanding of the cytoskeletal evolution in red algae (and plants more broadly) by conducting an initial study of the cytoskeleton in Rhodelphis limneticus, a motile and predatory organism that belongs to a phylum sister to red algae. In Project 2, in vitro evolution experiments will be carried out, with the goal of testing the hypothesis (developed through discussions with collaborators in population genetics and mathematical biology) that constraints imposed by nutrient availability affect the rate of adaptation to non-nutrient stresses. This pilot project has relevance for development of resistance to pesticides and drugs. Together, these parallel projects are designed to build a solid foundation for future research in experimental evolutionary cell biology.
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.
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0.915 |