The long-term goal of my research is to understand the mechanisms that control the recognition and phagocytic removal of apoptotic cells inside animal bodies. During an animal's development and adulthood, cells undergoing apoptosis, a cell suicide process, are rapidly internalized inside other cells via the process of phagocytosis, and are quickly degraded. Phagocytosis of apoptotic cells is an evolutionarily conserved process that plays pivotal roles in health. It is important for tissue remodeling, prevention and resolution of inflammatory and autoimmune responses, and repair of tissue injury. This proposal aims at revealing how engulfing cells in the nematode C. elegans recognizes apoptotic cells. In particular, it proposes to investigate how apoptotic C. elegans cells generate and present eat me signal(s) onto their outer surfaces, and how CED-1, an engulfing cell surface receptor identified by my previous research, recognizes the """"""""eat me"""""""" signal(s) and activates engulfment. CED-1 is similar to mammalian Scavenger Receptor from Endothelial Cells (SREC) and may possess ligand-binding specificities similar to that of scavenger receptors. Phosphatidylserine (PS), a phospholipid, has been implicated as a candidate """"""""eat me"""""""" signal for phagocytosis by studies in mammalian cell culture and by my research in C. elegans.
Specific Aim 1 proposes to dissect the functions of the extracellular domain of CED-1 by deletional and mutational analyses, aiming at learning how CED-1 binds to apoptotic cells and how this binding induces membrane bound CED-1 to cluster around apoptotic cells.
Specific Aim 2 proposes to study the function of CED-7, a C. elegans homolog of mammalian ABC (ATP-binding cassette) transporters. CED-7 function is required for CED-1 to recognize apoptotic cells. Whether CED-7 acts in the apoptotic or engulfing cells for this function and furthermore, whether CED-7 acts to present the eat me signal(s) will be examined.
Specific Aim 3 proposes to identify genes required for CED-1 to recognize apoptotic cells through genetic analyses. Studies of such genes will identify the eat me signal(s) and molecules required for its generation and presentation, and molecules that assist CED-1 to function as a receptor for the eat me signal(s). In the future, these C. elegans genes will help us identify and understand the functions of their mammalian counterparts in the clearance of apoptotic cells.
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