Members of the Apoptosis &Cell Death Research Program direct their attention towards fundamental molecular mechanisms of apoptotic cell death and translational research, operating under a model where the major technologies of modern biomedical research (cell and molecular biology, biochemistry, chemistry, and structural biology) are encompassed within the Program. All protein families that constitute the core of cell death signaling are covered in depth and constitute the existing four themes of the program, from the death receptors and death initiating signaling complexes (theme 1), to the caspases (theme 2), the Inhibitors of Apoptosis Proteins (lAPs;theme 3), and the Bcl-2 family members, including the integration of cell death signaling by mitochondria (theme 4). Increasing emphasis is also being placed on non-apoptotic forms of cell death as a developing theme. This past funding period has also witnessed the growth of a robust new series of collaborations within the Program that use the combined talents of the program members to identify small molecule cancer therapeutics targeting anti-apoptotic proteins. The overarching objective of the program is to provide an environment where reagents, techniques and ideas are shared to enhance the discovery process of the basic mechanisms that regulate the death cell fate decision. The Program has grown since the last renewal by the recruitment of two new full faculty members and one adjunct member with expertise that complements the interests of the original faculty members, and has maintained a leadership position in the fast-paced field of apoptosis and cell death research. Dr. Guy Salvesen continues as the Program Leader. The Program is highly collaborative and interactive with joint laboratory meetings, joint mentoring of graduate students and postdoctoral fellows, monthly trainee presentations, monthly faculty meetings, and participation and leadership in several Program Project grants and other collaborative funding mechanisms. As a result. Program funding is strong with current total annual grant funding of $22.9MM ($13.4MM direct). Program members lead or participate in 5 POIs (4 from NCI), and 10 U54/U19/U01 grants (3 from NCI) and several other federal and state collaborative grants, further attesting to high-level of collaborative activity in the program. Program's productivity is further reflected by 523 publications since last review, and by 96 Program publications in 2008, which represent 17% of intraand 13% of inter-programmatic collaborations, respectively.

Public Health Relevance

Defects in the regulation of the cell death machinery occur commonly in cancer, where too little cell death contributes to initiation and propagation of the transformed state. Most existing and potential cancer treatments appear to work through apoptosis, and resistance to apoptotic cell death is now recognized as a major contributor to failure in cancer therapy. Knowledge of the cell death mechanisms will provide insights into our understanding of tumor propagation, and will provide new targets for cancer therapeutics.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Center Core Grants (P30)
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Subcommittee G - Education (NCI)
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Sanford-Burnham Medical Research Institute
La Jolla
United States
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Lechtenberg, Bernhard C; Rajput, Akhil; Sanishvili, Ruslan et al. (2016) Structure of a HOIP/E2~ubiquitin complex reveals RBR E3 ligase mechanism and regulation. Nature 529:546-50
Zhong, Zhenyu; Umemura, Atsushi; Sanchez-Lopez, Elsa et al. (2016) NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria. Cell 164:896-910
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Koh, Mei Yee; Gagea, Mihai; Sargis, Timothy et al. (2016) A new HIF-1α/RANTES-driven pathway to hepatocellular carcinoma mediated by germline haploinsufficiency of SART1/HAF in mice. Hepatology 63:1576-91

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