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: 9576370
• 负责人: Veena Prahlad
• 金额: $ 32.83万
• 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/9576370
• 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线粒体体内平衡需要维持神经元健康和功能，其功能及其 2失调在使特定的神经系统易受伤害中起着突出的作用。最近 3我们发现p38有丝分裂原激活蛋白激酶的激活（MAPK； 4个哺乳动物P38α直系同源物）和类似CREB的转录因子ATF-7介导的先天 秀丽隐杆线虫肠中的5个免疫途径可以保护其神经元免受变性 6通过线粒体功能障碍诱导。 p38mapk/atf-7的神经保护作用 7在肠道中激活的免疫力是通过线粒体的增强而发生的，并且 仅肠细胞中的8 p38mapk/atf-7活性就足以降低线粒体数， 9不仅在肠细胞中，而且在神经元中。此外，在我们的实验室中获得的初步数据 10表明，在秀丽隐杆线虫中，与疾病相关的错误折叠蛋白的周围增加可以 11破坏先天免疫信号通路。因此，我们的中心假设是 12衰老和蛋白毒性引起的免疫系统失调会破坏 13神经元中的线粒体稳态引发或加剧了神经变性。 14拟议研究的目的是确定p38mapk/atf-7介导的 秀丽隐杆线虫中激活的15先天免疫途径会影响线粒体稳态 16个神经元。为此，我们将： 17 18目标1：检查先天免疫反应在维持神经元中的作用 19在复杂的I功能障碍时。 20 AIM 2：确定肠道中影响神经元健康的免疫介质。 21 AIM 3：检查周围蛋白毒性抗原在破坏免疫信号传导中的作用， 22导致神经元线粒体功能失调的积累。 23 24我们的初步数据表明，先天免疫反应调节线粒体 25细胞以非自治方式的体内平衡，而特异性可以抑制 26外周蛋白毒性抗原。因此，这些研究提供了一种新颖的可能性 27免疫衰老是导致线粒体功能失调的积累和 28可以为蛋白毒性在线粒体调节中的作用提供新的见解 29稳态。