2006 — 2010 |
Parvin, Jeffrey D |
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. |
Centrosomes and Brca1
Why mutations in the BRCA1 gene result in breast and ovarian cancer is unknown. Recent data from this laboratory suggest that the ubiquitination activity of the BRCA1 tumor suppressor regulates the duplication and function of centrosomes specifically in mammary epithelial cells in tissue culture. Using a transient assay to inhibit BRCA1 function, we have not observed centrosome amplification in cell lines derived from non- breast tissue. Centrosome amplification has been observed in the earliest and most aggressive breast cancer lesions, and it is likely that this function of BRCA1 is critical in the etiology of these tumors. Our data has revealed a new biological pathway, which controls centrosome number and function and which depends on the function of BRCA1 in breast cells. This project will dissect the BRCA1 function via three aims. 1.) Polypeptide targets of BRCA1 ubiquitination will be identified from centrosomes purified from breast cell lines. Proteins modified by the BRCA1-dependent ubiquitination activity will be assayed for effects on centrosome duplication. 2.) The effects of BRCA1-dependent ubiquitination on centrosome microtubule nucleation function will be assayed in vitro and in vivo, and the proteins and ubiquitinated substrates identified in aim 1 will also be tested for modulating the function of BRCA1 on this organelle. 3.) We will identify the factors in non-breast cells which render the BRCA1 ubiquitination activity redundant, and test whether the newly identified factor plus BRCA1 regulate centrosome amplification in these cell types. This project will identify the mechanism by which BRCA1 regulates centrosome duplication and centrosome function in breast cells. One of the earliest changes in the cells in an incipient breast cancer is a problem with the cellular machine that segregates the DNA when the breast cell divides. Research in this laboratory has found that the function of this machine, called a centrosome, is controlled in breast cells by the BRCA1 protein. This project will dissect the workings of the centrosome and determine how BRCA1 controls its function in normal cells, and we will learn how this process is changed when BRCA1 function is lost by mutation as happens in breast cancer.
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0.914 |
2009 — 2013 |
Catalyurek, Umit V. (co-PI) [⬀] Huang, Kun Parvin, Jeffrey D |
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. |
Informatics Methods For Identifying Breast Cancer Control Genes and Proteins
DESCRIPTION (provided by applicant): This project will develop a new framework for discovery of genes involved in the breast carcinogenesis process. Among families that have a predisposition to breast cancer, approximately 25% have inherited mutations in either breast cancer ("BRCA") genes BRCA1 or BRCA2, but the predisposing mutated genes in the majority of the families are unknown. BRCA1 and BRCA2 gene products both regulate cell division pathways that involve DNA repair and centrosome duplication, and their expression is correlated in microarray analyses in many cell types. We hypothesize that other unidentified BRCA genes may be involved in the same pathways that BRCA1 and BRCA2 regulate, and thus may be discovered by identifying genes whose expression also is correlated with that of BRCA1 and BRCA2. We will interrogate public-domain gene expression databases using newly developed computational tools that include combinatorial and algebraic clustering methods to identify genes whose expression correlates with these tumor suppressors. RNA interference will be used to disrupt the expression of the candidate BRCA gene products in two cell-based assays that are dependent on BRCA1 and BRCA2 expression. The first assay models the regulation of homology-directed recombination repair of double-strand DNA breaks, and the second assay tests the control of duplication of the centrosome. We will also perform a third test to determine whether the informatics-identified candidate BRCA gene product can form a protein complex with BRCA1 since several of the already identified co-expressed genes do form a complex with BRCA1. Candidate BRCA genes that are positive in the functional cell based assays will then be tested for changes in expression of their gene products in clinical samples, using an antibody-based, high-throughput tissue microarray system. In summary, this proposal outlines a novel experimental framework that will develop new bioinformatic tools for identifying candidate genes whose regulation suggests the potential for involvement in breast carcinogenesis, testing whether depletion of the proteins encoded by these candidate genes results in phenotypes in the laboratory that are consistent with breast cancer, and determining whether the expression of these candidate genes in clinical samples indicates their potential as biomarkers for breast carcinogenesis. This project defines a framework that may also be applicable to the identification of groups of genes involved in common pathways in other disease processes. PUBLIC HEALTH RELEVANCE: Among families that have a predisposition to breast cancer, approximately 25% have inherited mutations in either breast cancer ("BRCA") genes BRCA1 or BRCA2, but the predisposing mutated genes in the majority of the families are unknown. BRCA1 and BRCA2 gene products both regulate cell division pathways that involve DNA repair and centrosome duplication, and their expression is correlated in microarray analyses in many cell types. We hypothesize that other unidentified BRCA genes may be involved in the same pathways that BRCA1 and BRCA2 regulate, and thus may be discovered by identifying genes whose expression also is correlated with that of BRCA1 and BRCA2. These candidate BRCA genes will be identified through computer-program driven analyses of publicly available gene expression data. Candidate BRCA genes identified using these computer-based approaches will then be screened in laboratory tests using RNA interference assays to identify candidates that regulate homology-directed recombination repair of double-strand DNA breaks and/or centrosome duplication. Candidate BRCA genes that are validated in the laboratory will then be tested for changes in expression of their gene product using high-throughput labeled antibody assays in clinical samples. Thus, this proposal outlines a novel experimental framework that starts with a broad computer-based screen of gene expression libraries to identify initial candidates, performs a second screening using in vitro laboratory analyses of function, and then a third screen using expression in clinical samples. Genes that pass all three screens would be excellent candidates for genes that are responsible for breast cancer disposition in families, that may serve as biomarkers for the diagnosis of breast cancer, and that may contribute predictive value for the success of treatment modalities for an individual patient.
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0.914 |
2012 — 2016 |
Parvin, Jeffrey D |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Bioinformatics
The principal objective of the Bioinformatics Core will be to provide project investigators a resource for bioinformatics analysis and interpretation of high throughput experiments performed in each project. In support of this objective, the specific aims of the Bioinformatics Core B include: 1. Analysis of ChlP-seq results 2. Analysis of microarray or RNA-seq measures of mRNA and miRNA abundance 3. Identify biological networks that operate among different cell types in the tumor microenvironment 4. Develop decision-making tools for TME biomarkers and human relevance
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0.914 |
2012 — 2015 |
Parvin, Jeffrey D |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Biomedical Informatics
PROJECT SUMMARY (See instructions): The mission of the OSUCCC Biomedical Informatics Shared Resource (BISR) is to advance cancer research throughout the OSUCCC by providing end-users with advanced biomedical informatics services and expertise. End-users include OSUCCC leadership, investigators, research staff, trainees, and other shared resources (SRs) and scientific programs (SPs). In the last CCSG award cycle, the BISR was a developing shared resource and in this cycle will serve as a full shared resource. The BISR accomplishes its mission through a number of mechanisms, including the following specific services: 1) customization, deployment, and management of caBIG technologies and platforms in support of clinical and bio-molecular data management and integration requirements; 2) the execution of complex data analyses that require bioinformatics and computational-biology expertise; and 3) biomedical informatics consulting, project planning, and training. The BISR is organized into two complementary arms, focusing on Computational Biology Services (CBS) and Data Management Services (DMS). The CBS arm of the BISR provides end-users with services, including the planning and execution of SP- or SR-specific data management applications and analytical workflows, with an emphasis on the utilization of high throughput biological data, such as that generated by OSUCCC instrumentation SRs. The DMS arm of the BISR provides technical services and expertise in support of the adoption, customization, and use of caBIG technologies and platforms to facilitate SP- and SR-specific data management requirements, with an emphasis on the provision of data-analytic pipelines that enable end-users to identify, integrate, exchange, and analyze heterogeneous and distributed data sets/sources. In addition, the DMS arm facilitates OSUCCC end-user access to enterprise-wide clinical informatics tools and data sources, such as the Medical Center's Information Warehouse (a comprehensive enterprise-wide data warehouse), as well as the data management tools and resources being developed by the CTSA-funded OSU Center for Clinical and Translational Science (CCTS). The BISR serves as a catalyst throughout the OSUCCC to integrate and rapidly translate discoveries from the lab to cancer treatment and prevention.
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0.914 |
2016 — 2020 |
Parvin, Jeffrey D |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Biomedical Informatics Shared Resource
CORE-008 ? BIOMEDICAL INFORMATICS SHARED RESOURCE (BISR) PROJECT SUMMARY / ABSTRACT The OSUCCC Biomedical Informatics Shared Resource (BISR) provides a comprehensive suite of services, technologies and expertise that collectively support the resource-efficient conduct of basic, clinical/translational and population science for OSUCCC investigators. The Specific Aims of the BISR are: 1) to provide state-of- the-art bioinformatics and computational biology services for the analysis of massively parallel sequence data and the analysis of microarray datasets; 2) to provide OSUCCC investigators with services, expertise and access to technology platforms in support of heterogeneous and multi-dimensional biomedical data management requirements., The BISR, directed by Drs. Jeff Parvin (Aim 1) and Philip Payne (Aim 2), is supported through a combination of CCSG and project-specific grant funds (via charge-back mechanisms), as well as significant and ongoing institutional commitments of human, computational, and financial resources. During the prior five year grant period, the BISR was used by 45 OSUCCC members (59% of total users), but they accounted for 95.7% of usage. The BISR contributed to 195 publications, 29 with a journal impact factor greater than 10 and supported 21 NCI grants through billable services (charegebacks) (1 K12, 1 K24, 4 P01s, 2 P50s, 7 R01s, 1 R21, 1 R37, 1 RC2, 1 U01, 1 U10, and 1 U54). This is in addition to 18 BISR (Aim 1) staff members who have had directly funded appointments on NCI grants (i.e., 3 P01s, 2 P50s, 8 R01s, 1 R21, 1 RC2, 4 U01s, and 1 U54), other grants, and/or OSUCCC institutional funding sources. Through this work, BISR supported investigators from all five of the OSUCCC research programs. The BISR works closely and coordinates services with other OSUCCC shared resources, namely the Behavioral Measurement Shared Resource, the Genomics Shared Resource, the Biostatistics Shared Resource and the Biospecimen Services Shared Resource with its Total Care Cancer protocol. The future plans of the BISR are to streamline and strengthen existing next generation sequencing (NGS) data analysis pipelines through integration of new commercial programs, establish novel data visualization and visual analytics platforms, enhance the OSUCCC researchers abilities to access clinical data through an OSUCCC Information Warehouse serving as the honest broker and employing innovative electronic data capture tools, and fully implementing the Total Cancer Care protocol integration with other cancer centers for real time access to larger sets of electronic health records linked to biospecimens. The BISR leverages extensive institutional support and seeks only 7.0% support from CCSG funds. The Biomedical Informatics Shared Resource is part of the Analytics Grouping.
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0.914 |
2016 — 2017 |
Freitas, Michael A. Parvin, Jeffrey D |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Brca1 Interacting Proteins Important For Dna Repair
? DESCRIPTION (provided by applicant): We have analyzed for function in DNA repair a large panel of BRCA1 missense substitutions derived from a large number of cancer cases, and we found that when the pathogenic mutants were mapped onto the three-dimensional structure of the BRCA1 BRCT domain and of the BRCA1-BARD1 RING domains that they formed clusters. While many non-functional mutants could be explained by prior knowledge, two epitopes on the surface of the amino-terminal RING domain and one epitope on the surface of the carboxy-terminal BRCT domain have unknown function. In the case of the cluster on the BRCT domain, we hypothesize that it is a hitherto unknown protein binding site on the opposite face of the protein from the already known phosphoprotein binding site important for DNA repair. Similarly, the two epitopes in the amino-terminus of BRCA1 are likely protein-protein interaction sites with unknown binding partners, but we do know that these sites are critical for DNA repair function. We conclude that these cancer-associated mutations define novel protein binding sites that are important for BRCA1 function in DNA repair and for tumor suppression activity. This project will identify proteins that bind to BRCA1 dependent upon these epitopes. Since the mutation of these amino acids impairs BRCA1 function in DNA repair and tumor suppression, we anticipate that the proteins that bind to these amino acids will be tumor suppressors and DNA repair factors. In this early phase project, we will identify the proteins that bind to these epitopes by comparing proteins purified from wild-type versus specific mutant BRCA1 proteins. We will utilize quantitative mass spectrometry, which is the most sensitive method to detect such an interaction. Identified proteins will be analyzed/validated for function in DNA repair and will be analyzed in cancer databases for potential mutations in tumors. This project will identify one, or several, proteins that bind to each epitope, validate them for DNA repair function, and will enable a larger study that delves into the potential tumor suppressor function of the identified proteins and further characterizes the DNA repair function initially identified as an outcome of this project.
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0.914 |
2018 — 2020 |
Parvin, Jeffrey D |
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. |
Integrative Training in Biomedical Systems
Abstract The goal of the NIGMS-sponsored Systems and Integrative Biology (SIB) Training Program at The Ohio State University College of Medicine (OSU COM) is to educate an elite set of graduate students in the research approaches and competencies required for interdisciplinary basic and translational research. The Program explores mechanisms of cellular and complex organ systems, how their disruption leads to disease, and how the integration of disciplinary approaches in basic and medical sciences can lead to new discoveries that impact human health. It is coordinated with the broader COM effort within our medical center to generate discoveries that improve people?s lives through innovation in education and research. Our objective is to provide predoctoral trainees with an interdisciplinary curriculum that maintains high standards of intellectual rigor, fosters creativity and passion for research, and provides research opportunities with selected faculty that cross traditional disciplinary boundaries. The SIB Program was designed as an integral component of the larger Biomedical Sciences Graduate Program (BSGP), our parent Ph.D. training program, that provides high quality training opportunities to prepare our BSGP and MSTP graduates for successful careers in biomedical research. We are requesting funds for training six SIB predoctoral students per year for years 1 and 2 and eight SIB trainees per year for years 3-5, including three newly chosen trainees who have completed their first year in the BSGP core curriculum and three trainees who have completed one year in the SIB Program and compete for a one year renewal. Institutional support is provided. Coursework in analytics, workshops in team? building and communications skills, seminars, grant writing, training in the responsible conduct of research, and focus in two or more of eleven areas-of-research emphasis with vetted faculty members are the mechanisms by which the SIB Program provides collaborative and interdisciplinary training opportunities. The SIB Program faculty lead biomedical science research teams who are committed to student education and training, and who embrace the vision of diversity and cooperation in our academic research community. We are also committed to maintaining geographic and ethnic diversity in our Program through targeted recruitment and retention. In summary, the SIB Program will impart the interdisciplinary knowledge and skills to enable trainees to embrace our research mission and position themselves as leaders in a wide range of biomedical science careers.
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0.914 |
2019 — 2021 |
Parvin, Jeffrey D |
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. |
Multiplexed Functional Analysis of Brca1and Bard1 Missense Variants in Dna Repair
Multiplexed functional analysis of BRCA1 and BARD1 missense variants in DNA repair ABSTRACT Variants of unknown significance (VUS) are, in general, missense variants for which the interpretation of phenotypic impact is trapped in the void between pathogenic and benign. Any of these amino acid substitutions could cause major damage to the structure or molecular function of the encoded protein and therefore significantly impact disease risk, or it could have no effect all. Nowhere is the problem of VUS more apparent than in genetic testing for hereditary breast and ovarian cancer where published VUS rates range from 2-42% depending on the company doing testing/variant calling and number of genes included on the panel. For BRCA1 alone, there are 1020 VUS listed in the clinical genetics database, ClinVar. To address the problem of VUS interpretation, which is required to make genetic test results more useful for more patients, functional assays could be used to understand how each variant affects protein function. However, performing a post hoc functional assay for each variant as it is discovered is impossible at the current rate of accumulation. Here we propose to use deep mutational scanning to determine the functional impact of all possible missense variants in BRCA1 and BARD1 on their function in DNA repair in human cells. Our approach, developed in collaboration between our labs at Ohio State University and the University of Washington, measures the functional capacity of hundreds of protein variants in parallel in a homology directed DNA double strand break repair assay. The outcome of this project will have two deliverables: The first is an understanding of the sequence?function relationships, at single amino acid resolution, of two tumor suppressors in their role protecting the genome from DNA double strand breaks. The second outcome is a ?look up table? for the functional impact of any possible missense variant in BRCA1 and BARD1 that can be used by clinical geneticists to aid interpretation for variants that have been identified previously and those that have not yet been seen in the clinic.
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0.914 |