Nuclear and chromatin aberrations during non-apoptotic cell death in C. elegans and mammals

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Project Summary/ Abstract The long-term goal of the proposed research is to uncover molecular mechanisms driving non- apoptotic cell death in vertebrate development and disease, specifically the role of nuclear and chromatin organization in this process. Programed cell death functions to sculpt organs, remodel tissues, regulate cell number, and remove defective cells. While apoptosis is the most studied type of cell death, it does not account for all cellular destruction during development. Studies in C. elegans have uncovered a novel developmental cell death program, referred to as linker cell-type death (LCD), which is morphologically and molecularly distinct from apoptosis. Cell death with LCD features is commonly observed during vertebrate development and in neurodegenerative polyglutamine diseases, aggressive cancers, aging, progeria and laminopathies. During my postdoctoral training, I uncovered striking nuclear and chromatin changes that occur during LCD. This K99/R00 proposal seeks to identify the molecular regulatory processes underlying these nuclear and chromatin changes during LCD in C. elegans, and to test the functional conservation of LCD in a vertebrate context through the following specific aims: 1) Elucidate the role of nuclear lamin and its regulation in the process of LCD (K99); 2) Establish a mouse model system to study LCD in a developmental mammalian setting using degenerating Mullerian duct as a model (K99/R00); 3) Identify molecular processes that govern chromatin dynamics during LCD in C. elegans and mammals (R00). This proposal builds on my doctoral studies in mammalian epigenetics and chromatin, as well as postdoctoral training investigating non-apoptotic cell death in C. elegans. During the mentored phase, I will gain essential training in mouse organ culture and management, which will set me up to establish a robust and innovative independent research program studying the contribution of chromatin and nucleus to the non-apoptotic cell death in vertebrate and invertebrate systems, in addition to human disease. The outstanding environment at the Rockefeller University, with mentorship from Dr. Shaham and my Advisory Committee, will provide crucial expertise to facilitate my transition to independence. The studies proposed here will lead to the development of new markers to distinguish among different types of cell death in vertebrate development and disease, while uncovering the molecular underpinnings of LCD. Because LCD is a prevalent type of cell demise, this proposal may not only shed light on basic aspects of development, neurodegeneration, and cancer, but could also eventually uncover in-roads of clinical significance.