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

• 批准号: 9764236
• 负责人: Veena Prahlad
• 金额: $ 32.82万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764236
• 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; Immune response; Immune signaling; Immune system; Immunity; Infiltration; Innate Immune Response; Intestines; Lead; MAP Kinase Gene; MAPK14 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; insight; misfolded protein; mitochondrial dysfunction; mitogen-activated protein kinase p38; neuroprotection; novel; optogenetics; pathogen; proteotoxicity; relating to nervous system; response

1 Mitochondrial homeostasis is required to maintain neuronal health and function, and its 2 dysregulation plays prominent roles in rendering specific neural systems vulnerable. Recently 3 we have found that the activation of the p38 mitogen-activated protein kinase (MAPK; the 4 mammalian p38α ortholog) and the CREB like transcription factor ATF-7-mediated innate 5 immune pathway in the intestine of C. elegans can protect its neurons from degeneration 6 induced by mitochondrial dysfunction. The neuroprotective effects of p38MAPK/ATF-7 7 immunity activated in the gut occurs through the enhancement of mitophagy, and 8 p38MAPK/ATF-7 activity in intestinal cells alone is sufficient to lower mitochondrial numbers, 9 not only in intestinal cells, but also in neurons. Moreover, preliminary data obtained in our lab 10 show that in C. elegans the peripheral increase in disease-related misfolded proteins can 11 disrupt innate immune signaling pathways. Our central hypothesis, therefore, is that 12 aging- and proteotoxicity-induced dysregulation of the immune system can disrupt 13 mitochondrial homeostasis in neurons initiating or aggravating neurodegeneration. 14 The objective of the proposed research is to determine how the p38MAPK/ATF-7-mediated 15 innate immune pathway activated in the gut in C. elegans affects mitochondrial homeostasis 16 in neurons. To do this, we will: 17 18 Aim 1: Examine the role of the innate immune response in the maintenance of neurons 19 upon Complex I dysfunction. 20 Aim 2: Identify the immune mediators in the gut that affect neuronal health. 21 Aim 3: Examine the role of peripheral proteotoxic antigens in disrupting immune signaling, 22 leading to the accumulation of dysfunctional neuronal mitochondria. 23 24 Our preliminary data show that the innate immune response modulates mitochondrial 25 homeostasis in a cell non-autonomous manner, and is in turn can be inhibited by specific 26 peripheral proteotoxic antigens. These studies therefore offer the novel possibility that 27 immunosenescence is responsible for the accumulation of dysfunctional mitochondria, and 28 could offer new insights into the role of proteotoxicity in the modulation of mitochondrial 29 homeostasis.

1线粒体动态平衡是维持神经元健康和功能所必需的，其 2调节失调在使特定神经系统脆弱方面起着突出的作用。最近 3我们发现p38丝裂原活化蛋白激酶(MAPK； 4哺乳动物p38α同源基因)和CREB样转录因子atf-7介导的先天 线虫肠道免疫途径对其神经元的保护作用 6线粒体功能障碍。P38MAPK/ATF-7的神经保护作用 肠道中激活的免疫力是通过增强有丝分裂的吞噬作用而发生的。 仅肠道细胞中p38MAPK/ATF-7的活性就足以降低线粒体的数量， 9不仅存在于肠道细胞中，也存在于神经元中。此外，我们实验室获得的初步数据 10表明，在线虫中，与疾病相关的错误折叠蛋白的外周增加可以 11扰乱先天免疫信号通路。因此，我们的中心假设是 12衰老和蛋白毒性导致的免疫系统失调可扰乱 13启动或加重神经变性的神经元线粒体动态平衡。 14拟议研究的目的是确定p38MAPK/ATF-7如何介导 线虫肠道内激活的15种天然免疫途径影响线粒体动态平衡 16在神经元中。为此，我们将： 17 目的1：研究先天免疫反应在神经元维持中的作用 19关于复合体I功能障碍。 目标2：确定肠道中影响神经元健康的免疫介质。 21目标3：研究外周蛋白毒性抗原在破坏免疫信号中的作用， 22导致功能障碍的神经元线粒体堆积。 23 24我们的初步数据显示，先天免疫反应调节线粒体 25以一种细胞非自主的方式实现内稳态，进而可以被特定的 26个外周蛋白毒性抗原。因此，这些研究提供了一种新的可能性 27免疫衰老是导致功能失调的线粒体积累的原因，以及 28可以为蛋白质毒性在线粒体调控中的作用提供新的见解 29动态平衡。