As a normal aspect of animal development and tissue homeostasis, 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 and long-term objectives of this application are to understand the basic mechanisms underlying the control and execution of apoptosis and to use knowledge from such studies to develop new methods to treat and prevent apoptosis-related human diseases, especially caner. Chromosome fragmentation is a hallmark of apoptosis and a critical step in cell death execution. During apoptosis, a battery of nucleases are activated and act cooperatively and sequentially to promote fragmentation of chromosomal DNA. Seven new cell death-related nucleases (CRN nucleases) have been identified in C. elegans and found to act in at least two distinct pathways and two different functioning sites to promote DNA degradation and clearance of apoptotic cells during apoptosis. The goal of this application is to carry out biochemical, molecglar genetic, and cell biological studies in C. elegans to dissect the apoptotic DNA degradation machinery and to unravel the basic molecular mechanisms that regulate the execution of apoptotic DNA degradation and clearance of apoptotic cells.
The specific aims are: 1) to carry out biochemical, molecular genetic, and functional analyses of C. elegans crn genes to understand how they work together to promote apoptotic DNA degradation; 2) to identify and characterize additional genes that are important for apoptotic DNA degradation; 3) to investigate how the chromosome fragmentation process affects clearance of apoptotic cells, another critical cell death execution event involved in tissue remodeling, suppression of inflammation, and regulation of immune reponses. The studies of the molecular components and biochemical mechanisms that regulate chromatin degradation and cell clearance during apoptosis will provide crucial insights into how cell death is executed and should contribute to the understanding of the basic mechanisms that regulate apoptosis in general. ? ? ?
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