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The molecular mechanism of LCD, a prevalent and conserved non-apoptotic cell death program

LCD是一种普遍且保守的非凋亡细胞死亡程序的分子机制

基本信息

批准号：
9909508
负责人：
Olga Yarychkivska
金额：
$ 6.53万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9909508
关键词：
Adult Apoptosis Apoptotic Automobile Driving Binding Biological Assay Biological Models CRISPR screen Caenorhabditis elegans Caspase Cell Count Cell Culture System Cell Culture Techniques Cell Death Cells Cessation of life Cloaca Chamber Computer Analysis Cullin Proteins Cultured Cells Data Development Disease Embryo Event Exhibits Fellowship Fibroblasts Fingers Genes Genetic Genetic Epistasis Goals Gonadal structure Huntington Disease Hybrids Infarction Invertebrates Kinetics Knowledge Lead Light Lobular Neoplasia Malignant Neoplasms Mammalian Cell Methods Microscopy Mitogen-Activated Protein Kinase Kinases Molecular Molecular Target Morphology Mus Mutant Strains Mice Nerve Degeneration Organ Pathway interactions Patients Peptide Hydrolases Positioning Attribute Proteins Regulation Research Research Design Role Staurosporine System Testing Time Tissues Training Ubiquitin Vertebrates WNT Signaling Pathway Yeasts axonal degeneration base cell type clinically significant design human disease innovation male mouse model multicatalytic endopeptidase complex novel novel marker novel therapeutics polyglutamine polyglutamine neurodegenerative diseases programs protein aggregation sperm cell therapeutic development transcription factor ubiquitin-protein ligase whole genome

项目摘要

Project Summary/ Abstract The long-term goal of the proposed research is to uncover molecular mechanism driving non-apoptotic cell death in vertebrate development and disease. 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 patients and mouse models of neurodegenerative polyglutamine diseases. This proposal seeks to identify molecular events driving LCD in C. elegans, and to test their functional conservation in vertebrate settings. To rigorously investigate these mechanisms, this F32 proposal combines training in genetics, microscopy and computational analysis in vertebrate and invertebrate model systems to investigate the following specific aims: 1) identify molecular targets of the Ubiquitin Proteasome System (UPS) that precipitate cell destruction during LCD in C. elegans by performing functional studies and a yeast 2-hybrid screen; 2) uncover the molecular basis of LCD in vertebrates by developing a cell culture assay, testing roles of homologs of C. elegans LCD genes, and conducting a whole-genome CRISPR/Cas9 screen in cultured mammalian cells. 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.

项目摘要/摘要