As a normal aspect of animal development and homeostasis, programmed cell death (apoptosis) plays an essential role in maintaining the physiological balance of appropriate cell numbers by opposing uncontrolled cell proliferation. Abnormal inactivation or activation of apoptosis can lead to uncontrolled cell growth or uncontrolled cell death and may result in human diseases such as cancer, neurodegenerative diseases, and autoimmune disorders. The broad, long-term objective of this application is to understand the molecular mechanisms underlying the control and the execution of apoptosis and to use the knowledge from the study of apoptosis to facilitate development of new methods in treatment and prevention of human diseases caused by inappropriate cell death. ? ? Apoptosis is controlled and executed by an evolutionarily conserved cell death pathway. At the heart of this pathway is a family of highly specific """"""""death"""""""" proteases, the caspases, which are first synthesized as inactive protease precursors and later activated through proteolysis during apoptosis. The activation of death proteases triggers systematic and orderly cell-disassembly events. Several genetic suppressor screens have been carried out to identify downstream targets or components of the C. elegans CED-3 cell death protease and have led to the identification of at least 14 new cell death genes (cps genes, CED-3 protease suppressors) that act downstream of, or in parallel to, CED-3 to mediate various cell death execution events, including apoptotic DNA degradation and cell corpse engulfment.
The specific aims of this application are to carry out: (1) further genetic analyses of cps genes and cps mutants that we identified; (2) molecular and functional characterization of cps genes involved in apoptotic DNA degradation; (3) molecular and functional characterization of cps genes involved in cell corpse recognition/engulfment; and (4) molecular and functional characterization of cps genes involved in other death execution events. These studies should allow us to systematically identify molecular components and pathways involved in cell death execution and their functioning mechanisms. ? ?
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