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Cell Non-Autonomous Regulation of NeuronalProteostasis

神经元蛋白质稳态的细胞非自主调节

基本信息

批准号：
10359732
负责人：
Corinne Pender
金额：
$ 4.79万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
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：
2020-02-14 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10359732
关键词：
Adult Affect Age Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Animals Behavioral Blood Brain Caenorhabditis elegans Cell physiology Cells Cellular Stress Response Clinical Cognition Communication Cytoprotection Defect Development Disease Endoplasmic Reticulum Environment Epidermis Exercise Genes Goals Health Heat-Shock Response Inflammation Intestines Laboratories Lead Life Literature Longevity Mediating Memory Mentorship Mitochondria Modeling Molecular Mus Muscle Natural regeneration Nature Nervous system structure Neurodegenerative Disorders Neuroglia Neurons Obesity Organism Parabiosis Pathway interactions Peripheral Phenotype Physiology Proteins Proteome RNA Interference Regulation Research Research Personnel Role Signal Transduction Stress Temperature Testing Therapeutic Intervention Tissues Toxic Environmental Substances Training Transcript Work age related base biological adaptation to stress cell injury cell type experimental study feeding gene function improved insight knock-down mouse model new therapeutic target normal aging novel pathogen proteostasis proteotoxicity response screening sensor skills stressor transcriptome

项目摘要

Project Summary The capacity to response to internal and external stressors is critical for cellular survival throughout life and during aging. Despite the presence of protective mechanisms, cellular damage accrues over an organism’s lifetime, including accumulated damage to the proteome. Such deficits to protein homeostasis have a particularly deleterious effect in neurons, where they contribute to the development and progression of age-associated neurodegenerative diseases, such as Alzheimer’s disease. Cell-intrinsic mechanisms for responding to proteotoxicity have been identified; three major stress responses (the cytoplasmic heat shock response, the endoplasmic reticulum unfolded protein response, and the mitochondrial unfolded protein response) act cell autonomously in neurons and other cell types to ameliorate proteotoxic stress. There is also mounting evidence that neuronal health in this context is modulated by communication from non-neuronal tissues; however, very little is known about the relevant underlying mechanisms. The major objective of the proposed work is to characterize the nature of cell non-autonomous regulation of neuronal proteostasis, using C. elegans as a model. First, we will determine how perturbing stress response pathways in non-neuronal tissues affect neuronal proteostasis. Recent work has shown that activation of each of the three proteostatic stress responses in neurons cell non- autonomously protects peripheral tissues from proteotoxicity; we hypothesize that non-autonomous protection might also occur in the reverse direction, i.e. that activation of these stress responses in non-neuronal tissues can promote neuronal proteostasis, which we will test by in Aim 1. Second, we will more broadly explore mechanisms of periphery-to-neuron communication that alter neuronal proteostasis. We will identify genes that function cell non-autonomously to regulate neuronal proteostasis using a tissue-specific knockdown screening approach in Aim 2. Together these aims are likely to yield insight into the mechanisms by which inter-tissue communication influences neuronal health and could lead to the identification of new therapeutic targets for diseases associated with neuronal proteotoxic stress. The sponsor for the proposed work, Dr. Andrew Dillin, is a renowned expert in proteostasis with an excellent training record; his laboratory at UC Berkeley represents an ideal environment for the applicant to develop the research, mentorship, and communication skills necessary to become an independent investigator.

项目总结