2014 — 2021 |
Johnson, David G. [⬀] Mcbride, Kevin Michael |
R25Activity Code Description: For support to develop and/or implement a program as it relates to a category in one or more of the areas of education, information, training, technical assistance, coordination, or evaluation. |
Md Anderson Science Park Summer Program in Cancer Research Spcr @ University of Tx Md Anderson Can Ctr
PROJECT SUMMARY The goal of the Summer Program in Cancer Research (SPCR) is to provide talented undergraduate students with a research project-based laboratory experience and exposure to different science and health disciplines working to address the causes, diagnosis, prevention, and treatment of cancer. The Program objective is to promote careers in cancer research and clinical oncology, which is in line with the NCI mission to attract and train the best minds to become the next generation of cancer researchers. This goal will be accomplished through a formalized 10-week program during which participants will work on an individualized research project under the supervision of a faculty mentor. The MD Anderson Science Park campus in Smithville, Texas, provides a unique environment for young scientists to engage in cutting-edge research using state-of-the-art technologies while working in a park-like setting. Participating faculty members are not only committed educators but also internationally recognized experts in the fields of cancer genetics and genomics, epigenetics, DNA repair and mutagenesis, stem cells, immunology, and mechanisms of cell death and survival. Students will also gain an appreciation for other areas of cancer biology, such as viral carcinogenesis, angiogenesis, and metastasis, through a Program lecture series complemented by additional lectures video conferenced from Houston designed for all summer students at MD Anderson. An appreciation for the wide variety of research being performed at MD Anderson will also be gained through field trip experiences to the MD Anderson main campus and hospital in Houston and the Keeling Center for Comparative Medicine. Students will be exposed to the variety of career options available to individuals interested in cancer research through career development lectures and a Careers in Science Panel Discussion. Students will also learn how to organize a scientific presentation, including background information, hypothesis, methods, results, and conclusions, and will hone their oral communication skills in preparation for a culminating Scientific Symposium, where students present their research projects to departmental faculty, trainees, and staff. Past programmatic evaluations demonstrate that the SPCR is an important contributor to the career development of participating students and influenced their decision and ability to pursue graduate or other training leading to careers in cancer-related research and medicine.
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0.943 |
2014 — 2015 |
Krug, Laurie T [⬀] Mcbride, Kevin Michael |
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.) |
Uracil Dna Glycosylases in Herpesvirus Pathogenesis and Dna Mutation @ State University New York Stony Brook
DESCRIPTION (provided by applicant): Uracil DNA glycosylase (UNG) is an enzyme that removes misincorporated and mutagenic uracils, leaving an abasic site typically repaired by the host base excision repair pathway. Each herpesvirus encodes a viral UNG, but we know little regarding the function of this highly conserved gene in the virus lifecycle. Studies indicate that herpesvirus vUNGs interact with components of the viral DNA replication machinery and promote late stage replication events in primary or quiescent cells. The vUNG of herpes simplex virus has been reported to enhance herpes simplex virus latency in mice, but the role of vUNG in a full pathogenic course of gammaherpesvirus infection in a natural host has not been reported. The gammaherpesviruses Epstein-Barr virus, Kaposi's sarcoma-associated herpesvirus, and the mouse model pathogen murine gammaherpesvirus 68 establish latency in immunoglobulin class-switched B cells; infection can lead to immortalization and transformation of B cells. Host UNG2 activity is required for generating the diverse antibody repertoire of B cells, but also triggers chromosome translocations that are the etiology of lymphomas. Thus, alterations of uracil glycoslyase activity may tip the balance between immunity and malignancy. This proposal is to understand how the UNGs encoded by the gammaherpesviruses promote viral pathogenesis and impact the B cell antibody repertoire and lymphomagenesis of the host. In Aim 1, the impact of viral and host UNG on promoting the integrity of the viral genome in the process of lytic replication will be determined. In addition, we will examine changes in the pathogenesis of MHV68¿vUNG in the presence or absence of host UNG2 to determine the contribution of viral and host UNG to replication, latency, and reactivation in vivo. In Aim 2, we will address whether viral UNG promotes mutagenic outcomes such as immunoglobulin gene class-switch recombination and somatic hypermutation, off-target mutations in oncogenes, or translocations such as c-myc/Ig translocations that define EBV+ Burkitt's lymphoma. Our studies might uncover an interaction of viral UNG with the host cytidine deaminase AID that will provide critical insight regarding the molecular etiology of ¿HV cancers.
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1 |
2016 — 2020 |
Mcbride, Kevin Michael |
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. |
Uracil Dna Glycosylases in Gammaherpesvirus Pathogenesis and B Cell Development @ University of Tx Md Anderson Can Ctr
Project Summary Each herpesvirus encodes a viral homolog of mammalian uracil DNA glycosylase (vUNG). Mammalian UNG is an enzyme that removes misincorporated and mutagenic uracils, leaving an abasic site typically repaired by the host base excision repair pathways. Although there is conserved sequence and in vitro activity between vUNG and host UNG, little is known regarding vUNG function in the virus lifecycle or effect on host genome DNA repair. Studies indicate that herpesvirus vUNG may interact with components of the viral DNA replication machinery; however, its role in late stage replication events in primary cells is uncertain. We utilize murine gammaherpesvirus 68 (MHV68) as a mouse model for human gammaherpesviruses, Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus. Our studies indicate that herpesvirus vUNG plays a critical role in pathogenesis, as vUNG deficient virus has major replication and infectivity defects. Gammaherpesvirus infects germinal center (GC) B cells and establishes latency in memory B cells, a process that can lead to immortalization and transformation of B cells. In GC B cells, host UNG activity process AID induced uracils to trigger antibody diversification, a process that also triggers chromosome translocations that are associated with lymphomas. Our studies indicate vUNG can process uracil in genomic DNA but with repair outcome different than host UNG. vUNG suppresses antibody mutation and class switch recombination in a manner that is both catalytic and non-catalytic dependent suggesting a scaffold function for vUNG. Thus, vUNG has the potential to contribute to altered viral pathogenesis, immunity and malignancy. We propose studies to understand how vUNG promotes viral pathogenesis and subverts host antibody diversification. In Aim 1, the structural and biochemical basis for error-free repair of DNA lesions by vUNG will be investigated. Differences between vUNG and host UNG will be characterized to determine the domains and interacting partners that result in differential error-free versus error-prone repair outcome. In Aim 2, the mechanisms by which vUNG promotes gammaherpesvirus pathogenesis will be investigated. The contribution of vUNG enzymatic function and scaffold functions will be characterized. In Aim 3, the impact of gammaherpesvirus infection and vUNG on B cell development will be investigated. B cell activation and immunoglobulin repertoire will be examined during MHV68 infection. Antibody repertoire and self-reactivity will be analyzed during acute infection and latency reactivation. Our aims straddle molecular immunology and molecular virology in the fields of gammaherpesvirus pathogenesis and B cell biology. The proposed studies should elucidate the mechanism by which vUNG supports viral replication, infection, and viral subversion of immunoglobulin diversification.
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0.945 |