1973 — 1977 |
Gorenstein, David |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Monomeric Metaphosphate Vs the Pentacovalent Phosphorus Intermediate @ University of Illinois At Chicago |
0.915 |
1977 — 1980 |
Gorenstein, David |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Stereoelectronic Control in the Reactions of Phosphate Esters @ University of Illinois At Chicago |
0.915 |
1982 — 1985 |
Gorenstein, David |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Stereoelectronic Effects in Organophosphorus Compounds (Chemistry) @ University of Illinois At Chicago |
0.915 |
1985 — 1988 |
Gorenstein, David G. |
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. |
Nmr Studies of Nucleic Acids and Nucleic Acid Complexes @ Purdue University West Lafayette
Nuclear magnetic resonance (NMR) spectroscopy will provide an important probe of the detailed chemical structure and dynamics of nucleic acids (DNA, RNA, tRNA) and nucleic acid complexes. NMR is virtually a unique technique capable of providing an understanding of the chemical basis of genetic diseases and the structural basis for protein, carcinogen, and drug binding to nucleic acids. We have recently proposed that 31P chemical shifts are sensitive to the conformation about phosphate ester bonds. The 31P NMR spectra will thus provide a powerful probe of conformation of nucleic acids and nucleic acid drug and nucleic acid carcinogen complexes. We will consider the 31P NMR spectra of double-helical nucleic acids and, in particular, spectral changes in going from a "B" DNA to a "Z" DNA conformation. The latter has been implicated in possible carcinogen activation of genes. Phosphorus NMR spectra of transfer RNA will be used to provide support to the hypothesis that these molecules exist in at least two conformations, which has been suggested to be important in protein biosynthesis. The conformational changes upon lac repressor headpiece binding to a 14 base pair DNA lac operator fragment will be probed by 31P NMR. In the nucleic acid systems all oligonucleotides, thiophosphoryl and 170-phosphoryl) oligonucleotides, and covalently modified oligonucleotides will be chemically synthesized by the phosphoramite method on solid supports.
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1 |
1985 — 1986 |
Gorenstein, David G. |
P41Activity Code Description: Undocumented code - click on the grant title for more information. |
A Regional Nmr Resource For Biomedical Research @ Purdue University West Lafayette
Continued support is requested for a regional high-resolution NMR facility for the study of biological systems housed in the Department of Chemistry, Purdue University. The Facility is designed to handle the severe problems of resolution and sensitivity encountered with biological macromolecules. The research proposals submitted by users of the Facility cover several general areas: structure and function of proteins, nucleic acids, membranes, and natural products; active sites of enzymes; modes of action of drugs; and physiological levels of metabolites in living cells and organisms. The Facility is based on two multinuclear spectrometers, 11.1 T narrow-bore and 4.7 T wide-bore. The efficiencies of these will be increased by adding computer controlled field shims and an off-line data processing station, which will be used for training and core research. The versatility of the Facility will be expanded by the addition of broad-banded probes and instrumentation for saturation transfer, laser CIDNP, and selective relaxation experiments. Although the primary function of the Facility is to provide an effective research tool to its users, part of the efforts of its staff are directed toward technological development in the areas of probe sensitivity, efficient multinuclear operation, variable temperature operation, custom probes for specialized experiments, and effective processing, storage, and presentation of spectra. The Facility is administered by an Advisory Committee consisting of the Principal Investigator, representative users, and nationally recognized experts in the field. Service time on the spectrometers is apportioned according to the scientific merit of the research as determined by the Advisory Committee.
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1 |
1986 — 1989 |
Gorenstein, David G. |
P41Activity Code Description: Undocumented code - click on the grant title for more information. |
A Regional Resource For Biochemical Research @ Purdue University West Lafayette
Continued support is requested for a regional high-resolution NMR facility for the study of biological systems housed in the Department of Chemistry, Purdue University. The Facility is designed to handle the severe problems of resolution and sensitivity encountered with biological macromolecules. The research proposals submitted by users of the Facility cover several general areas: structure and function of proteins, nucleic acids, membranes, and natural products; active sites of enzymes; modes of action of drugs; and physiological levels of metabolites in living cells and organisms. The Facility is based on two multinuclear spectrometers, 11.1 T narrow-bore and 4.7 T wide-bore. The efficiencies of these will be increased by adding computer controlled field shims and an off-line data processing station, which will be used for training and core research. The versatility of the Facility will be expanded by the addition of broad-banded probes and instrumentation for saturation transfer, laser CIDNP, and selective relaxation experiments. Although the primary function of the Facility is to provide an effective research tool to its users, part of the efforts of its staff are directed toward technological development in the areas of probe sensitivity, efficient multinuclear operation, variable temperature operation, custom probes for specialized experiments, and effective processing, storage, and presentation of spectra. The Facility is administered by an Advisory Committee consisting of the Principal Investigator, representative users, and nationally recognized experts in the field. Service time on the spectrometers is apportioned according to the scientific merit of the research as determined by the Advisory Committee.
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1 |
1987 — 1990 |
Jorgensen, William Jones, Claude Santini, Robert Gorenstein, David |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Center For Biomolecular Nmr, Structure, and Design
This proposal requests funds to establish a Biological Facilities Center in state.of.the.art high.resolution NMR and computer graphics/molecular modeling methodologies to determine the 3D solution structure and dynamics of biomolecules. The Center will provide the infrastructure support for a diverse range ofprojects requiring NMR, molecular modeling, molecular mechanics/dynamics and perturbational free energy calculations to design new biomolecules. Initially the Center's focus will be on the study and design of proteins, modified DNA analogs and DNA binding drugs and proteins. In a number of projects, these "designed" biomolecules will be synthesized using established synthetic organic methods or through automated DNA or oligopeptide synthesizers. Alternatively, recombinant DNA methdologies will be used to genetically engineer mutant proteins. The Center will then determine the 3D structure of the designed biomolecules via 2D NMR nd distance geometry methods and compare the structure with that predicted by the calculations and modeling. Structure and activity of the designed biomoleculeswill be compared to better understand the biological activity of these biomolecules. This center will benefit a large and diverse group of researchers, estimated at about l20 faculty members. Thus, it has considerable potential for fostering interactions of unique combinations of multidisciplinary talent.
|
0.915 |
1988 — 1990 |
Gorenstein, David |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Acquisition of a 600 Nmr Spectrometer
This proposal requests partial funding to purchase a 600 NMR spectrometer that will be used by ten major users and seven minor users. The spectrometer will support a variety of research, ranging from NMR studies of protein-nucleic acid and peptide- metal complexes to determinations of the structures of intermediates in organic and biological synthesis of biomolecules. The sensitivity and resolution of this instrument will significantly enhance the type of information that will be obtained from biomolecular NMR studies. Joint support from the Instrumentation and Instrument Development and Chemical Instrument Programs is recommended.
|
0.915 |
1989 — 1992 |
Gorenstein, David G. |
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. |
Nmr, Structure and Design of Hiv Regulatory Agents @ Purdue University West Lafayette
human immunodeficiency virus; antiAIDS agent; antiviral agents; chemical synthesis; peptide chemical synthesis; virus protein; DNA binding protein; phosphonate; antisense nucleic acid; AIDS; genetic transcription; molecular pathology; chemical structure function; nucleic acid chemical synthesis; nuclear magnetic resonance spectroscopy; genetic operator element; gene induction /repression; mathematical model; complementary DNA; oligonucleotides; messenger RNA; X ray crystallography; mutant;
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1 |
1993 — 1999 |
Gorenstein, David G. |
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. |
Nmr and Design of Antisense and Ribozyme Agents to Hiv @ University of Texas Medical Br Galveston
DESCRIPTION: (Adapted from Applicant's Abstract) Multi-dimensional high resolution nuclear magnetic resonance (NMR) spectroscopy and restrained molecular dynamics will be used to define the three-dimensional structure of antisense, sense and ribozyme oligonucleotide agents, and nucleic acid-agent complexes targeted towards the human immunodeficiency (AIDS) virus. Diasteromerically pure phosphorothioates and phosphorodithioate oligonucleotide analogues will be synthesized and the three-dimensional structure of their complexes with complementary single-stranded oligonucleotides in duplex, ribozyme and three-stranded junctions will be determined to understand the in vitro and in vivo biological activities that will also be obtained. The investigators will also design, synthesize and structurally characterize sense (or decoy) oligonucleotide analogues targeted to HIV-1 reverse transcriptase. Various RNA and DNA agents will be synthesized using established synthetic organic methods. They will take an integrated approach towards the rational design of agents targeted towards HIV utilizing NMR, computational biochemistry, and molecular modeling of nucleic acid agents. NMR spectroscopy will provide an important probe of the molecular structure and dynamics of these macromolecules and their target complexes. Finally they will utilize folate receptor mediated endocytosis to effectively deliver backbone modified, liposomal encapsulated agents targeted to the epidermal growth factor receptor directly into the cytoplasm of human cells. This should help avoid problems associated with most other delivery methods that end up compartmentalizing the agents, often into the lysosomes where they are degraded. Ultimately the investigators hope to rationally design and construct agents to inhibit HIV-1 proliferation and gene expression.
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1 |
1997 |
Gorenstein, David G. |
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. |
Mechanism of Dna Repair Enzymes @ University of Texas Medical Br Galveston
Because DNA polymerase beta (Beta-pol) is responsible for gap-filling synthesis in some mammalian DNA repair pathways, it is one of the most important enzymes for maintaining the integrity of genomic DNA. B-pol is a potential target for drug design to either enhance or block the DNA repair process. However, our understanding of the molecular mechanisms of B-pol is in its infancy, so that we do not yet know enough to develop a program of rational drug design. To correct this deficiency, and to understand basic principles of the nucleotidyltransferase reaction of DNA polymerases, we will focus on a key step in the B-pol DNA synthesis mechanism, enzyme-template.primer binding. The project exploits recombinant expression of B-pol and its constituent domains in E. coli and involves: 1) Studies of the molecular structure of B-pol both by X- ray crystallography and by multidimensional NMR spectroscopy. B-pol and its domain fragments will be crystallized as complexes with the synthetic primer d(T) and with other synthetic template primers. NMR analysis will be with B-pol fragments ranging from -6 to 12- kDa, representing folded protease-resistant domains in the intact protein. Structures obtained by these approaches will be examined for implications on function by molecular modeling and site-directed mutagenesis, followed by functional assays of mutant proteins; 2) Studies of B-pol functions, such as binding to template primer and primer substrates: These will use equilibrium binding and enzymological techniques, including pre-steady kinetics. The enzyme-template.primer binding pocket, localized by photochemical cross- linking and structural studies, will be altered by site-directed mutagenesis. Studies of replication by B-pol will seek the cause of sequence variability among products of DNA synthesis by B-pol. Frameshaft mutational hot spots account for much of the variability, a process probably due to mistakes that are initiated by template.primer slippage mechanisms. We will study mutations produced in vitro to determine if template.primer-B-pol interactions play a role in the template.primer slippage. One goal of drug design targeted to B-pol is to develop agents that can potentiate chemotherapy by inhibiting DNA repair. Since gap- filling synthesis is required during repair of many types of DNA lesions, B-pol is a logical choice for drug intervention. A second goal of drug design is enhancing DNA repair by finding agents that increase the activity and/or accuracy of B-pol.
|
0.984 |
2000 — 2004 |
Gorenstein, David G. |
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. |
Combinatorial &Rational Design Aptamers Targeting Hiv @ University of Texas Medical Br Galveston
Novel combinatorial and structure-based design methods will be used to develop phosphorothioate and phosphorodithioate DNA decoys or aptamers as targeted therapeutics towards the human immunodeficiency virus (HIV). Development of these anti-AIDS agents will be facilitated by nuclear magnetic resonance (NMR) spectroscopy and computational biochemistry of both agent and protein agent complexes. We will specifically synthesize thioated backbone aptamer oligonucleotide analogues targeted to HIV-1 reverse transcriptase (RT) and nucleocapsid (NCp7) and the human transcription factor NF-kappaB. We have recently developed a novel combinatorial selection scheme for phosphorothioate hybrid backbone aptamers targeting the nuclear factor for human IL6 (NF-IL6), a transcription factor involved in the induction of acute-phase responsive and cytokine gene promoters in response to inflammation. Using a random combinatorial selection approach and dNTP(alpha)S s in PCR amplification, we have selected specific thio-substituted agents which have the highest specificity in binding (nM range) to NF-IL6. This is currently being extended to NF-kappaB and will also be applied to NCp7 and RT. A split synthesis scheme will be developed for combinatorial selection of dithiophosphate aptamers for these proteins. Since phosphorothioate and phosphorodithioate substituted oligonucleotides show reduced nuclease activity, these combinatorial thiophosphate-selection experiments can offer wide application for rapid identification of new therapeutic agents. This technology will allow us to develop separate aptamers targeting in principle any one of the 15 possible combinations of 5 homo- and heterodimers of the 5 different forms of NF-kappaB/Rel. NF-kappaB/Rel transcription factors, are key mediators of the immune and acute phase responses, apoptosis, cell proliferation and differentiation, and are key transactivators acting on the LTR of HIV-1. They thus represent potential therapeutic targets for control of HIV-1 proliferation. NMR will be used to define the three-dimensional structure of monothio- and dithiophosphate modified oligonucleotide agents and aptamer NCp7 complexes. We will also assess the in vivo activity of the aptamers in tissue culture testing to arrest HIV-1 proliferation and gene expression as well as to activate HIV gene expression to identify hidden reservoirs of infection. Finally, we will explore the feasibility of utilizing these highly selective thioaptamers for recognition of protein-protein interactions using a new DNA/protein chip technology for genetic analysis at the level of functional protein expression.
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0.984 |
2003 — 2007 |
Gorenstein, David G |
U01Activity 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. |
Biodefense Proteomics Collaboratory @ University of Texas Medical Br Galveston
DESCRIPTION (provided by applicant): In vitro enzymatic combinatorial selection and split-synthesis chemical combinatorial methods will be used to develop a "ThioAptamer Chip" (TACh) for proteomics - a diagnostic tool to identify and quantify the differential expression of key proteins in response to pathogens of concern for bioterrorism threat (BT). This new proteomics technology will utilize our proprietary thioselection and phosphorothioate-modified oligonucleotide "thioaptamers," combined with the surface enhanced laser desorption/ionization (SELDI) mass spectroscopy technology of our collaborating partner, Ciphergen, to target both rodent and human proteomes. In particular we will study the inflammatory response of cytokines and key transcription factors (e.g., NF-kappaB) challenged with BT agents. The five NF-?B/Rel family proteins can combine to form 15 homo- and heterodimers, each performing a specific signaling function upon translocation across the cell nuclear membrane and binding to a gene's promoter region. In partnership with Ciphergen, we will also develop new, massively parallel, thioaptamer bead-based screening of the proteome with SELDI mass-spectrometric methods to identify uncharacterized proteins involved in the immune response to BT viruses. Our results from the TACh/SELDI approaches will be validated by 2D gel mass spectrometric proteomic methods. We will also apply bioinformatic analyses to correlate changes in protein expression with available genomic data on changes in gene expression as a result of inflammation after viral infection or shock. Elucidating these protein expression changes will allow early diagnosis and enhanced prognosis of viral disease, and subsequent development of effective pharmacological and immunological interventions. Specific initial viral targets include arenaviruses, Pichinde and Lassa (the latter on both the NIH and CDC class A lists).
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1 |
2005 — 2007 |
Gorenstein, David G |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Computational and Structural Biology in Biodefense @ University of Texas Medical Br Galveston
[unreadable] DESCRIPTION (provided by applicant): We will establish a multidisciplinary predoctoral and postdoctoral Training Program in Computational and Structural Biology in Biodefense, spanning the fields of biochemistry, biophysics, molecular biology, structural biology, bioinformatics, genomics, proteomics, database management, chemical biology, cell biology, immunology, virology, and pathology. The last 20 years have seen a remarkable resurgence of infectious diseases and the emergence of new ones such as AIDS and SARS, as well as the new threat from bioterrorism. Consequently, there is a critical need to train first-rate, imaginative, and creative scientists in this multidisciplinary field. Strong emphasis will be placed on cross-training in these fields. The opportunities to develop new vaccines, therapeutics, and diagnostics for biothreat agents and emerging or reemerging infectious diseases have never been greater, and the need to develop interdisciplinary training never more important than today. This training grant application requests support for six predoctoral and four postdoctoral trainees; each trainee will be supported for a period of two years. Together with the research and infrastructure and training support provided by the W. M. Keck Center for Computational Biology of the Gulf Coast Consortia as well as the Western Regional Center of Excellence in Biodefense and Emerging Infectious Diseases and the Galveston National Laboratory, this number will provide an adequate critical mass of trainees for the base of 32 mentors in the program, as each trainee will be required to participate in interdisciplinary research, with a primary mentor and a secondary co-mentor, one in structural, computational or chemical biology and the other in a biomedical field related to biodefense and infectious diseases. Part of the success of this program is the team-based, multi-disciplinary, multi-institutional groups of scientists that have worked together now for over 14 years, consisting of researchers at Baylor College of Medicine, Rice U., U. of Houston, U. of Texas HSC, Houston M. D. Anderson Cancer Ctr., and UTMB Galveston. [unreadable] [unreadable]
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0.984 |
2007 |
Gorenstein, David G |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Combinatorial Selection of Beta-Catenin/T Cell Factor Pathway Inhibitors @ University of Texas Medical Br Galveston
[unreadable] DESCRIPTION (provided by applicant): Colorectal cancer (CRC), the second leading cause of cancer mortality in the United States, is preventable and curable when found in its early stages. Although several chemopreventive agents prevent CRC in experimental animal models, no agent has been approved for human use. Besides surgical resection, which is rarely curative in advanced disease, current therapy for colon cancer relies on traditional cytotoxic agents with limited effects. Our long-term goal is to develop modified oligonucleotides (ODNs) to provide innovative therapeutic products for the treatment of cancer, in particular CRC. The formation of a transcriptional complex between an oncogenic beta-catenin and a T cell factor (TCF) is believed to be a key event in CRC cell development. Agents that modulate this pathway and/or disrupt the beta-catenin and TCF interaction are likely to inhibit the subsequent expression of many target genes that leads to CRC. The goal of this project is to identify a tight-binding and highly specific ODN that will bind to the beta-catenin binding domain of human TCF4 (TCF-CBD) to block the beta-catenin binding with TCF and/or disrupt the beta-catenin and TCF interaction. Structure-based design and novel combinatorial selection will be used to achieve this goal. Three specific aims will be pursued: Aim (1) express, purify, and characterize the TCF-CBD protein; Aim (2) identify tightly binding and highly specific aptamers containing 5-aminoallyl-2'-deoxyuridine (5-AA-aptamers) targeting TCF-CBD; Aim (3) test the 5-AA-aptamers for disruption of the beta-catenin.TCF complex in vitro. These experiments should ultimately introduce new lead anti-CRC compounds. Such lead compounds will be tested in cell cultures and animal models. Our novel anticancer discovery and development strategy can be applied to other cancers. In addition, the results generated from this research will be used in an application for a future NIH RO1 grant. Lay abstract: Development of anticancer drugs has proven to be challenging. However, oligonucleotide- based inhibition drugs can be selected from a very large random pool (10[12] approximately 10[14] members) by their ability to bind a specific protein. This novel anticancer strategy is important because it should allow us to very rapidly discover highly effective drug compounds. [unreadable] [unreadable] [unreadable]
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0.984 |
2008 — 2011 |
Gorenstein, David G |
P41Activity Code Description: Undocumented code - click on the grant title for more information. |
Large Particle Sorting For the Selection of Optimal Aptamer Binders @ Los Alamos Nat Secty-Los Alamos Nat Lab
Affinity; Asthma; BSL-4 facility; BSL4 facility; Biologic Marker; Biological Markers; Biological Terrorism; Bioterrorism; Blood Serum; Bronchial Asthma; Bronchioalveolar Lavage; Bronchoalveolar Lavage; CRISP; Caliber; Cell model; Cellular model; Chemokine, Other; Circulatory Collapse; Collaborations; Color; Complex; Computer Retrieval of Information on Scientific Projects Database; Country; Cytofluorometry, Flow; Development; Diagnostic; Diameter; Disease Progression; Drug Design; Early Diagnosis; Flow Cytofluorometries; Flow Cytometry; Flow Microfluorimetry; Forecast of outcome; Funding; Generations; Goals; Grant; Human; Human, General; Immune response; Immunity, Innate; Immunity, Native; Immunity, Natural; Immunity, Non-Specific; Infection; Inflammatory Response; Institution; Investigators; Laboratories; Lavage, Bronchopulmonary; Libraries; Ligands; Lung Lavage; Man (Taxonomy); Man, Modern; Microfluorometry, Flow; Molecular Marker; NIH; National Institutes of Health; National Institutes of Health (U.S.); Natural Immunity; Numbers; Particle Size; Performance; Pichinde; Process; Prognosis; Programs (PT); Programs [Publication Type]; Progressive Disease; Proteins; Proteome; Proteomics; Range; Rate; Research; Research Personnel; Research Resources; Researchers; Resources; Rodent Model; Sampling; Serum; Shock; Signature Molecule; Sorting - Cell Movement; Source; Speed; Speed (motion); Technology; Testing; Therapeutic; Time; United States National Institutes of Health; Viral Diseases; Virus; Virus Diseases; Viruses, General; Work; aptamer; base; biodefense; biomarker; biosafety level 4 facility; bronchopulmonary lavage therapy; circulatory shock; cytokine; early detection; flow cytophotometry; gene product; hemorrhagic fever virus; host response; immunological intervention; immunoresponse; improved; instrument; interest; outcome forecast; particle; pathogen; programs; protein expression; prototype; response; sorting; tool; viral infection; virus infection
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0.919 |
2009 — 2010 |
Gorenstein, David G |
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. |
Role of Nitric Oxide and Cyclic Gmp in Stem Cells @ University of Texas Hlth Sci Ctr Houston
DESCRIPTION (provided by applicant): In this revised application, we will primarily focus on studying the role of NO and cyclic GMP signaling in proliferation and differentiation of human and mouse embryonic stem cells into cardiomyocytes. Our preliminary studies strongly suggest a role for nitric oxide and cyclic GMP in mouse and human embryonic stem cell proliferation and differentiation. The mRNA (RT-PCR and Northerns) and protein (Western and activity) in mouse and human stem cells (WA09) will be examined during stem cell proliferation and differentiation for nitric oxide synthases (NOS 1,2,3) and soluble guanylyl cyclase, the receptor for NO. The cellular localization will be confirmed with immunohistochemistry for these proteins and cellular markers and cell sorting. The effects of activators and inhibitors of NOS, soluble guanylyl cyclase, protein kinase G, and cyclic nucleotide phosphodieserases will also be examined to confirm the role of NO and cGMP in stem cell proliferation and differentiation into myocardial cells. With an understanding of the presence or absence of the proteins participating in nitric oxide and cyclic GMP synthesis and function in stem cells and differentiated cells with their in vitro culture, we expect to be able to design experimental protocols with various pharmacologic agents such as NO donor drugs, cyclic nucleotide analogues, phosphodieterase inhibitors, and guanylyl cyclase activators that should modify stem cell proliferation and differentiation into various cellular lineages. The function of these stem cells and differentiated cells will also be examined in several cardiovascular models. This should be extremely valuable information for future clinical studies by others and us for the purpose of tissue replacement and perhaps drug and gene delivery systems. Several colleagues with expertise in stem cell biology and/or in vivo animal models will serve as advisors, consultants, and collaborators. Our preliminary experiments and the work of others indicate that our studies proposed are feasible and are likely to be successful to determine the roles of nitric oxide and cyclic GMP in stem cell proliferation, differentiation, and function.
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1 |
2009 — 2010 |
Chiu, Wah (co-PI) [⬀] Decuzzi, Paolo Drezek, Rebekah A. (co-PI) [⬀] Ferrari, Mauro Gorenstein, David G Klostergaard, Jim (co-PI) [⬀] Li, Chun Lopez-Berestein, Gabriel (co-PI) [⬀] Sood, Anil K (co-PI) [⬀] Suh, Junghae (co-PI) [⬀] West, Jennifer L (co-PI) [⬀] Wilson, Lon |
RC2Activity Code Description: To support high impact ideas that may lay the foundation for new fields of investigation; accelerate breakthroughs; stimulate early and applied research on cutting-edge technologies; foster new approaches to improve the interactions among multi- and interdisciplinary research teams; or, advance the research enterprise in a way that could stimulate future growth and investments and advance public health and health care delivery. This activity code could support either a specific research question or propose the creation of a unique infrastructure/resource designed to accelerate scientific progress in the future. |
Subcellular Localization of Nanoparticles @ University of Texas Hlth Sci Ctr Houston
DESCRIPTION (provided by applicant): The overall goal of this initiative is to investigate the cellular uptake, trafficking, and sub-cellular localization of different classes and subtypes of nanoparticles (NPs) with well-defined physiochemical properties for the creation of a reference table that relates the sub-cellular distribution of NPs to their intrinsic physiochemical properties across a range of cell lines. The subcellular fate of NPs is relevant both in terms of the therapeutic efficacy and biosafety of the NPs. The effective impact of size, shape, charge, and chemical composition of nanomaterials, in the presence of serum opsonins, on both cellular entry and subsequent subcellular localization will be investigated. The expected outcome of this project is to create a reference table that accelerates the transition of nanomaterials from the bench to the clinic by rapidly expanding our knowledge of the effect of a material's intrinsic characteristics on its intracellular destination. The final product, a comprehensive table of NPs and their subcellular locations, will guide the future development of NP drug delivery systems for rapid expansion of biomedical applications, including cancer therapy, cardiovascular imaging, and gene therapy. PUBLIC HEALTH RELEVANCE: What this project seeks to deliver is a multi-dimensional reference table that relates the subcellular distribution and toxicity of NPs to their intrinsic physiochemical properties across a range of diverse cells and cell lines. It is our hope that the data generated from this project will serve as a resource for future research and encourage model development and new insights into nanotechnologies for imaging and drug delivery.
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1 |
2010 — 2014 |
Gorenstein, David G |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Targeting Core @ University of Texas Hlth Sci Ctr Houston
CORE TITLE: Targeting Core CORE SUMMARY: Traditionally, robust protein-specific targeting ligand requirements are met by antibodies (Abs). Antibodies however often have significant problems, including high cost, selection difficulties, selectivity problems, preparation difficulties, stability and immunogenicity. The Targeting Core objective is to provide the Projects in the TCCN sets of targeting reagents for the nanoparticles that not only includes "gold standard" antibodies but novel aptamers and peptides to both endothelial, cancer and stem cells, both to specific cell surface ligands as well as the cells themselves. All projects will use the resources from the Biological Targeting Core. Specifically, the Targeting Core will develop thioaptamers and next-generation Xaptamers for targeting nanoparticles to CD44 (Project 1;Aim 2), E-Selectin, (Project 1: Aim 2, Project 2: Aim 2), VGFR, EGFR, ICAM-1 and cells (Project 3: Aim 1) and peptides and antibodies via phage display for targeting proteins (Project 1;Aim 2) and cells (Project 3: Aim 1;Project 4: Aim 2). Additionally, the Targeting Core will provide conjugation of targeting ligands and all micro/nanoparticles (Projects 1-3).
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1 |
2010 — 2013 |
Ferrari, Mauro Gorenstein, David G Lopez-Berestein, Gabriel (co-PI) [⬀] Sood, Anil K (co-PI) [⬀] |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Texas Center For Cancer Nanomedicine @ University of Texas Hlth Sci Ctr Houston
The University of Texas Health Science Center at Houston (UTHSC-H), The University of Texas M.D. Anderson Cancer Center, Rice University and Albert Einstein College of Medicine have joined forces to form the Texas Center for Cancer Nanomedicine (TCCN). The TCCN brings together a multi-disciplinary, internationally recognized team of investigators to develop and translate nanotechnology-enabled innovation for improving the traditionally dismal outcome of ovarian and pancreatic cancers. The main research focus areas of the TCCN are: Multifunctional Nano-Therapeutics and Post-Therapy Monitoring Tools (Area 2 of the CCNE RFA), and Devices and Techniques for Cancer Prevention and Control (Area 3). By natural synergies of the underlying nano-platforms, the TCCN's investigations in focus areas 2 and 3 automatically provide a cadre of approaches for Area 1: Early Diagnosis Using In-Vitro Assays and Devices and In-Vivo Imaging Techniques. The TCCN has four projects and three cores. Projects 1 and 2 directly address ovarian cancer, and Projects 3 and 4 directly address pancreatic cancer. In each oncology focus area, one project involves multifunctional nanoplatforms for the delivery of bioactive agents to the tumors (Project 1- ovarian and Project 3- pancreatic), and the other, targeting approaches to the cancer-associated vascular endothelia (Project 2- ovarian and Project 4- pancreatic), for imaging and therapy. Both adenocarcinoma (Project 3) and endocrine pancreatic malignancies (Project 4) are considered in the TCCN. All Projects integrate fundamental investigations in cancer biology, nanotechnology platform development, and pharmaceutical sciences, albeit to different degrees. The cores are the Biomathematics Core, Targeting Core and Nanoengineering Core. All projects and Cores integrate with each other through the sharing of research results and nanotechnology platforms. This integration allows the TCCN to achieve clinical translation of its research breakthroughs, and aggressively manage the risks that are naturally associated with any highly innovative program at a rapid pace. To fuel translation to the clinic, several TCCN investigators have successfully developed spin-off companies based upon their research. Collectively, with a combination of synergistic projects supported by cores that provide services to each project and a track record of successful bench-to-bedside translation, the TCCN is uniquely positioned to bring forth highly effective nanotechnology platforms for prevention, therapy and monitoring of ovarian and pancreatic cancers. Public Health Relevance: The TCCN aims to utilize innovative nanotechnologies for new therapeutic strategies, methodologies for reliable monitoring of therapeutic efficacy, early detection approaches from biological fluids and advances in imaging, and cancer-prevention protocols for ovarian and pancreatic cancers. The TCCN will apply a diverse array of nano-platforms to achieve these aims. While the primary emphasis In the TCCN is on ovarian and pancreatic cancers, it is likely that the new approaches will have applications for many other malignancies.
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1 |
2014 |
Annapragada, Ananth V (co-PI) [⬀] Gorenstein, David G Vigneswaran, Nadarajah |
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. |
Aptamer Mediated Targeting of Fanconi Anemia Oral Cancer Initiating Cells @ University of Texas Hlth Sci Ctr Houston
Abstract: We seek to use a novel cell-internalization SELEX (Systemic Evolution of Ligands by Exponential enrichment) to isolate thioaptamer-conjugated liposomal nanoparticles (TA-NP) that internalize and deliver its siRNA into the cytosol of tumor initiating cells (TIC) of oral squamous cell carcinoma, minimizing off-target delivery. In vivo delivery and release of siRNA from the endosomes to cytosol remain the two biggest obstacles for translating anticancer siRNA drugs to the clinic. Oral squamous cell carcinoma commonly known as oral cancer (OC) is the most common malignancy of head and neck with high global public health impact. Fanconi anemia (FA) is a hereditary cancer syndrome that predisposes one to OC. Evidence points to TIC as the key driver of field cancerization, resistance to therapy and disease relapse. A therapeutic vehicle that selectively targets and delivers anticancer drugs to TIC offers great promise for OC treatment. Our data and published studies show: (1).TIC is more enriched in FA-OC than sporadic OC; (2) Chk1 and CD147 promote TIC survival and chemoresistance and its overexpression contribute to poor prognosis in OC. The main goal of this proposal is to use FA- OC-TIC as target cells to develop TA- NP for the cytosolic delivery of siRNA. We hypothesize that isolated TA-NP will facilitate targeted delivery of siRNA to OC-TIC cytosol, and silence CD-147/Chk1 in OC-TIC's, disrupting their niche and rendering them chemosensitive and susceptible to elimination by chemotherapy with gemcitabine. Aims:(1): Elucidate the effect of RNAi mediated silencing of CD147/Chk1 in FA-OC-TIC; (2A): Select a list of TA-Liposomal NP (TA-NP) specific for TIC fraction of FA-OC cells, while avoiding hepatocyte uptake, using a positive and negative cell-uptake based SELEX; (2B): Determine the selected TA-NP's targeting specificity and therapeutic efficacy in in vitro and in murine OC xenografts. We will isolate ALDH+ TIC in FA-OC cell lines and examine the effects of siRNA-mediated silencing of CD147 and Chk1. (2) We will use a modified conjugate SELEX with positive and negative selections to identify OC-TIC-specific internalizing TA-NP. (3) We will validate TIC-targeting specificity and silencing efficacy of isolated TA-NP-sRNA in vitro and in murine orthotopic FA-OC xenografts. RNAi mediated inhibition of CD147 and Chk1 in OC-TIC will yield valuable insight into their potential role in the tumor propagating and chemoresistant properties of OC-TIC. The proposed TA-NP will have important clinical potentials for in vivo delivery of therapeutic and imaging agents targeting the OC-TIC.
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