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Uncovering how serotonergic signaling non-autonomously regulates protein homeostasis

揭示血清素信号如何非自主调节蛋白质稳态

基本信息

批准号：
9904301
负责人：
Veena Prahlad
金额：
$ 29.74万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9904301
关键词：
Address Age Aging Alzheimer&apos s Disease Animal Model Animals Cells Cellular Stress Response Cessation of life Coupled Cytoprotection Disease Distal Drug Targeting Elements Functional disorder Gene Proteins Genes Genetic Screening Genetic Techniques HSF1 Health Heat shock proteins Heat-Shock Response Human Huntington Disease Image Impairment Intervention Laboratories Mammals Messenger RNA Nervous System control Neuroglia Neurons Neurosecretion Neurotransmitters Organism Parkinson Disease Pathway interactions Perception Proteins Resolution Sensory Serotonin Signal Pathway Signal Transduction Stress System Techniques Time Tissues Toxic effect Work age related biological adaptation to stress individual response innovation neurosensory neurotransmission novel optogenetics protein aggregation protein misfolding proteostasis public health relevance receptor response tissue stress transcription factor

项目摘要

DESCRIPTION (provided by applicant):"Proteinopathies," diseases of protein misfolding and aggregation, are debilitating age-related diseases such as ALS, Alzheimer's, Parkinson's and Huntington's Diseases, for which there are currently no interventions to reduce cell dysfunction and death. Harnessing the cell's own protective responses to protein misfolding such as the heat shock response (HSR) dramatically ameliorates the toxic effects of protein aggregation in all animal models of proteinopathies. Recent studies have shown that the HSR of individual cells of an organism is under non-autonomous control of the nervous system. The objective of this proposal is to determine precisely how neurons control the HSR in another cell. We have identified a crucial element of this cytoprotective mechanism: thermosensory-induced serotonin (5-hydroxytryptamine, 5-HT) release is necessary and sufficient to induce the HSR in other cells and thereby suppress protein aggregation and misfolding. We show this by live imaging of HSF-1, the transcription factor responsible for the expression of protective heat shock protein (HSP) genes, in combination with optogenetic excitation of specific neurons in intact animals. Using techniques developed in our laboratory, we will investigate the inter-tissue signaling mechanisms by which sensory stress perception results in cytoprotection. The innovation of the proposed work is that it will elucidate, in-depth, for the first time, a mechanism of cell non-autonomous control of the HSR. Aging results in the inevitable decline in an organism's ability to withstand stress. It is unclear whether decreases in the efficiency of stress signaling mechanisms themselves contribute to this aging-dependent impairment of stress responses. Our expertise in dissecting the mechanisms by which the neurosensory system signals stress to distal tissues, and non-autonomously controls their response allows us a unique opportunity to address this question. Hypothesis: Thermosensory-induced release of 5-HT activates adaptive cellular stress responses that protect protein homeostasis. Aim 1. How do thermosensory (AFD) neurons elicit 5-HT release from serotonergic neurons? Aim 2. What inter-tissue stress signaling pathways are activated by 5-HT in responsive cells?