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Investigating how intestinal innate immunity confers neuroprotection using C. elegans

使用线虫研究肠道先天免疫如何赋予神经保护作用

基本信息

批准号：
10425212
负责人：
Veena Prahlad
金额：
$ 33.49万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10425212
关键词：
Affect Aging Animals Antigens Autophagocytosis Biological Response Modifiers CREB1 gene Caenorhabditis elegans Cells Complex Data Disease Functional disorder Gene Expression Genes Genetic Health Homeostasis Immune response Immune signaling Immune system Immunity Infiltration Innate Immune Response Intestines Lead MAP Kinase Gene Maintenance Mammalian Cell Mediating Mitochondria Muscle Cells Mutation Natural Immunity Nematoda Nerve Degeneration Nervous system structure Neurons Orthologous Gene Pathway interactions Peripheral Play Predisposition Proteins RNA interference screen Research Role Rotenone Signal Pathway Signal Transduction System Tissues activating transcription factor alpha synuclein common cellular transcription factor ATF dopaminergic neuron gene product immunosenescence innate immune pathways insight misfolded protein mitochondrial dysfunction neuroprotection novel optogenetics p38 Mitogen Activated Protein Kinase pathogen proteotoxicity relating to nervous system response

项目摘要

Mitochondrial homeostasis is required to maintain neuronal health and function, and its dysregulation plays prominent roles in rendering specific neural systems vulnerable. Recently we have found that the activation of the p38 mitogen-activated protein kinase (MAPK; the mammalian p38α ortholog) and the CREB like transcription factor ATF-7-mediated innate immune pathway in the intestine of C. elegans can protect its neurons from degeneration induced by mitochondrial dysfunction. The neuroprotective effects of p38MAPK/ATF-7 immunity activated in the gut occurs through the enhancement of mitophagy, and p38MAPK/ATF-7 activity in intestinal cells alone is sufficient to lower mitochondrial numbers, not only in intestinal cells, but also in neurons. Moreover, preliminary data obtained in our lab show that in C. elegans the peripheral increase in disease-related misfolded proteins can disrupt innate immune signaling pathways. Our central hypothesis, therefore, is that aging- and proteotoxicity-induced dysregulation of the immune system can disrupt mitochondrial homeostasis in neurons initiating or aggravating neurodegeneration. The objective of the proposed research is to determine how the p38MAPK/ATF-7-mediated innate immune pathway activated in the gut in C. elegans affects mitochondrial homeostasis in neurons. To do this, we will: Aim 1: Examine the role of the innate immune response in the maintenance of neurons upon Complex I dysfunction. Aim 2: Identify the immune mediators in the gut that affect neuronal health. Aim 3: Examine the role of peripheral proteotoxic antigens in disrupting immune signaling, leading to the accumulation of dysfunctional neuronal mitochondria. Our preliminary data show that the innate immune response modulates mitochondrial homeostasis in a cell non-autonomous manner, and is in turn can be inhibited by specific peripheral proteotoxic antigens. These studies therefore offer the novel possibility that immunosenescence is responsible for the accumulation of dysfunctional mitochondria, and could offer new insights into the role of proteotoxicity in the modulation of mitochondrial homeostasis.

线粒体内稳态是维持神经元健康和功能所必需的