The intrinsic apoptosis pathway involves the disruption of mitochondria and the releases of mitochondrial proteins, leading to the activation of caspase-9 and a downstream caspase cascade. Although cell death can still proceed in the absence of caspase-9, it was delayed in casapse-9-deficient B cells with significant induction of autophagy. Experiments are proposed to test the hypothesis that the interplay between caspase-9 and autophagy plays an important role in regulating programmed cell death. Autophagy may help to protect against cell death by clearing damaged mitochondria: 1) To study the mechanisms for the rescue of caspase-9-deficient B cells after partial loss of mitochondrial membrane potential;2) To determine the mechanisms by which autophagy promotes the survival of B cells;and 3) To investigate the roles of caspase-9 and autophagy in the regulation of development and functions of lymphocytes in vivo. The interplays between caspase signaling and mitochondrial autophagy in regulating programmed cell death will be investigated. The proposed study will help to gain insights into the molecular mechanisms for the regulation of mitochondrial autophagy during cell death. Mitochondrial quality control by autophagy has been suggested to play essential roles in the prevention against aging, cancer and neurodegenerative diseases. The proposed study may facilitate the development of better strategies for treating diseases involving abnormal mitochondrial autophagy.

Public Health Relevance

This project seeks to investigate the regulation of programmed cell death by caspases and autophagy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM087710-09
Application #
8245167
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Marino, Pamela
Project Start
2003-07-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
9
Fiscal Year
2012
Total Cost
$338,502
Indirect Cost
$117,979
Name
Baylor College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Chen, Min; Hong, Monica Jeongsoo; Sun, Huanhuan et al. (2014) Essential role for autophagy in the maintenance of immunological memory against influenza infection. Nat Med 20:503-10
Guerrero, Alan D; Welschhans, Robert L; Chen, Min et al. (2013) Cleavage of anti-apoptotic Bcl-2 family members after TCR stimulation contributes to the decision between T cell activation and apoptosis. J Immunol 190:168-73
Chen, Min; Huang, Lily; Wang, Jin (2013) Analyses of programmed cell death in dendritic cells. Methods Mol Biol 979:51-63
Chen, Min; Felix, Kumar; Wang, Jin (2012) Critical role for perforin and Fas-dependent killing of dendritic cells in the control of inflammation. Blood 119:127-36
Chen, Min; Felix, Kumar; Wang, Jin (2011) Immune regulation through mitochondrion-dependent dendritic cell death induced by T regulatory cells. J Immunol 187:5684-92
Chen, Min; Wang, Jin (2010) Programmed cell death of dendritic cells in immune regulation. Immunol Rev 236:11-27
Chen, Min; Sandoval, Hector; Wang, Jin (2008) Selective mitochondrial autophagy during erythroid maturation. Autophagy 4:926-8