CIT ID: 6091
Program date: Friday, January 11, 2008, 10:00:00 AM
Presented by: Dan Roden, M.D., Vanderbilt University

Abstract:

OPASI ROUNDS Lecture Series

Administration of virtually any drug to a group of patient’s results in a spectrum of responses: some patients may derive great benefit, in others there is no effect, and some patients will have adverse effects. The concept that such variability in drug response might include a heritable component goes back over 100 years. The identification of responsible variants in individual genes, and the sequencing of the human genome and its variants now opens the door to an era of personalized prescribing in which genomic information becomes a routine component of clinical decision-making. This talk will highlight current evidence linking genomic variants to variable drug responses, and will describe obstacles – and their potential solutions – to the implementation of such a personalized prescribing future.

The Office of Portfolio Analysis and Strategic Initiatives (OPASI) provides the National Institutes of Health (NIH) and its constituent Institutes and Centers (ICs) with the methods and information necessary to manage their large and complex scientific portfolios, identifies – in concert with multiple other inputs – important areas of emerging scientific opportunities or rising public health challenges, and assists in the acceleration of investments in these areas, focusing on those involving multiple ICs.

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	Enhanced Audio Podcast	1:25:00			Enhanced Video Podcast	1:25:00

CIT ID: 6205
Program date: Wednesday, January 09, 2008, 3:00:00 PM
Presented by: Laurie Kaguni, Ph.D., Michigan State University

Abstract:

The mitochondrial replicase (pol gamma) comprises two subunits, a large catalytic core (pol gamma-alpha) and a smaller accessory subunit (pol gamma-betta) that enhances holoenzyme activity and processivity. Mutagenesis of four conserved sequence elements located within the spacer region between the DNA polymerase and 3'-5' exonuclease active sites in pol gamma-alpha demonstrates their functional roles in holoenzyme activity, processivity and/ or DNA binding affinity. Several mutations also affect differentially DNA polymerase and exonuclease activity, and/ or functional interactions with mitochondrial single-stranded DNA-binding protein (mtSSB). Overexpression of the catalytic core in the nervous system of Drosophila induces severe mtDNA depletion and reduces median life span. A parallel mutagenesis of the human accessory subunit, in combination with the determination of its crystal structure and molecular modeling, elucidates its role as a novel type of processivity factor. Loss of function alleles result in mtDNA depletion and developmental lethality in Drosophila. A human pol gamma/DNA complex model was developed using the structures of the pol gamma beta dimer and the T7 DNA polymerase ternary complex, which suggests multiple regions of subunit interaction between pol gamma beta and the human catalytic core that allow it to encircle the newly synthesized double-stranded DNA, and thereby enhance DNA binding affinity and holoenzyme processivity. Functional complexes of pol gamma, mtSSB and a novel mitochondrial DNA helicase reconstitute the mitochondrial DNA replication fork. The human mtDNA helicase exists as a hexamer/ heptamer and exhibits a modular architecture that is highly similar to that of bacteriophage T7 primase-helicase and E. coli DnaB protein. Molecular analysis of active site and selected human disease alleles of the Drosophila homolog by overexpression in Schneider cells results in a dominant-negative lethal phenotype resulting from mtDNA depletion. This work was supported by NIH grant GM45295.

Dr. Kaguni completed her B.A. degree in Biology with High Honors at the University of California, San Diego in 1974 and worked as a research assistant with Professor E. P. Geiduschek from 1974-1976. She completed her Ph.D. degree in Biology in the laboratory of Professor Dan S. Ray at the University of California, Los Angeles in 1980. Her Ph.D. research focused on the study of small phage replication and on the genetic elements and protein requirements for bacterial DNA replication. She pursued a year-long NIH-sponsored postdoctoral study in 1980 in the laboratory of Professor David Clayton at Stanford University studying site-directed pausing in DNA synthesis promoted by DNA secondary structure, and continued in 1981-1984 as an American Cancer Society postdoctoral fellow in the laboratory of Professor Robert Lehman at Stanford University, where she purified and characterized the first native form of animal DNA polymerase alpha-primase, elucidating its four-subunit structure and determining the subunit association of its two enzyme activities.

Dr. Kaguni was appointed as Assistant Professor in 1984 in the Department of Biochemistry at Michigan State University, where she currently holds the title of University Distinguished Professor. There she began her studies of the enzymology and molecular genetics of mitochondrial DNA replication, using the fruit fly Drosophila as and animal model system. Her laboratory has made seminal contributions to our understanding of the structure and functional roles of the mitochondrial DNA replicase, purifying the first native form, elucidating its subunit structure, characterizing its two catalytic activities, and cloning and expressing its two subunits and elucidating their functional roles.

For more information, visit
http://www.bch.msu.edu/faculty/kagunil.htm

NIH Director's Wednesday Afternoon Lecture

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CIT ID: 6174
Program date: Monday, January 07, 2008, 12:00:00 PM
Presented by: Don W. Cleveland, Ph. D., University of California, San Diego

Abstract:

NIH Neuroscience Seminar Series

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	Enhanced Audio Podcast	1:13:24			Enhanced Video Podcast	1:13:24

CIT ID: 6204
Program date: Wednesday, December 19, 2007, 3:00:00 PM
Presented by: Arlene Sharpe, Harvard Medical School

Abstract:

Dr. Sharpe's laboratory is interested in analyzing the role of costimulatory molecules in T cell activation in vivo. Costimulation is a pivotal event for T cell activation, determining the functional outcome of T cell interaction with antigen presenting cells (activation versus anergy). Her laboratory's work has focused on the obligatory in vivo role of costimulators using targeted gene disruption and have revealed striking and unexpected functions of costimulatory pathways. Analysis of B7-1 deficient mice provided the first evidence for the existence of additional functional CD28/CTLA-4 counter-receptors in vivo. As a result of these findings, a second CTLA-4 counter-receptor, B7-2, was cloned and revealed as the major early activating costimulator in this pathway. Mice lacking both B7-1 and B7-2 exhibit profound immunologic deficits. Together, these 3 B7 deficient strains have facilitated a comparative analysis of the in vivo functions of B7-1 and B7-2, as well as definitive tools for determining when the B7:CD28/CTLA-4 pathway is essential for T cell activation. Her CTLA-4 deficient mouse revealed a critical role for CTLA-4 in turning off activated T cells. This critical negative immunoregulatory function of CTLA-4 provides a previously unsuspected means by which costimulation can regulate responses to self antigens and potentially offers new approaches for manipulating activated T cells. More recently, she has studied the functions of newly discovered members of the B7-CD28 superfamily (ICOS:B7h and PD-1:PD-L1/PD-L2 pathways) and helped identify the P-D-1:PD-L1 pair as playing a key inhibitory role in immune suppression during chronic viral infection. Her talk today will focus on the role of PD-1 and its ligands in regulating T cell activation and tolerance, as well as the new PD-L1:B7-1 pathway.

Dr. Sharpe received her BA from Radcliffe College and her MD and PhD from Harvard Medical School where she worked with Dr. Bernie Fields on the genetics of reovirus replication. After a residency in pathology at Brigham and Women's Hospital, she worked with Dr. Rudi Jaenisch on pioneering studies of retroviral infection of embryos, as well as studies of induction of spongiform neurodegeneration by the Cas-Br-E retrovirus. Her training in mouse embryology and the use of embryonic stem cells strongly influenced the work in her own laboratory, where her studies have concentrated on the analysis of lymphocyte function in vivo using transgenic and 'knockout' mice. Dr. Sharpe's laboratory is a leader in the area of costimulation, a critical process in T cell activation that determines the functional outcome (activation versus anergy) of T cells after interaction with antigen presenting cells.

Dr. Sharpe is considered a world expert on costimulatory molecules and immune function. Her animals studies have played a central role in defining the in vivo physiological role of these molecules and the mice she has generated have been a key resource to the entire field, especially investigators examining the role of these pathways in diverse pathologic states. Her primary publications have appeared in high profile journals and her reviews are the standards in the field.

Dr. Sharpe is the George Fabyan Professor of Comparative Pathology at Harvard Medical School, the Director of the Immunology Research Division of the Brigham and Women's Hospital and the Vice-chair for Education in the Department of Pathology at Harvard Medical School. She was the recipient of the 2006 Distinguished Lecturer Award from the American Association of Immunologists and was elected to the American Academy of Arts and Sciences in 2007.

http://www.dfhcc.harvard.edu/membership/member-profile/member/321/0

The NIH Director's Wednesday Afternoon Lecture Series includes weekly scientific talks by some of the top researchers in the biomedical sciences worldwide.

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	Enhanced Audio Podcast	1:01:12			Enhanced Video Podcast	1:01:12

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