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

• 批准号: 9103670
• 负责人: Veena Prahlad
• 金额: $ 32.21万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9103670
• 关键词: Address; Age; Aging; Alzheimer' s Disease; Animal Model; Animals; CD2 Antigens; Cells; Cellular Stress Response; Cessation of life; Coupled; Cytoprotection; Disease; Distal; Drug Targeting; Elements; Functional disorder; Genes; Genetic Screening; Genetic Techniques; HSF1; Health; Heat shock proteins; Heat-Shock Response; Homeostasis; Human; Huntington Disease; Image; Impairment; Individual; Intervention; Laboratories; Life; 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; innovation; neurosensory; neurotransmission; novel; optogenetics; protein aggregation; protein misfolding; public health relevance; response; transcription factor

 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?

 描述（由申请人提供）：“蛋白质病”是蛋白质错误折叠和聚集的疾病，是使人衰弱的与年龄相关的疾病，例如肌萎缩性脊髓侧索硬化症、阿尔茨海默病、帕金森病和亨廷顿病，目前还没有针对这些疾病的干预措施来减少细胞功能障碍和死亡。利用细胞自身对蛋白质错误折叠的保护性反应，例如热休克反应（HSR），可以显着改善所有蛋白质病动物模型中蛋白质聚集的毒性作用。最近的研究表明，生物体单个细胞的 HSR 受到神经系统的非自主控制。该提案的目的是精确确定神经元如何控制另一个细胞中的 HSR。我们已经确定了这种细胞保护机制的一个关键要素：热感应诱导的血清素（5-羟色胺，5-HT）释放对于诱导其他细胞中的 HSR 是必要且充分的，从而抑制蛋白质聚集和错误折叠。我们通过HSF-1（负责保护性热休克蛋白（HSP）基因表达的转录因子）的实时成像结合完整动物中特定神经元的光遗传学激发来证明这一点。使用我们实验室开发的技术，我们将研究感觉应激感知导致细胞保护的组织间信号传导机制。该工作的创新之处在于，它将首次深入阐明HSR的细胞非自主控制机制。衰老导致有机体承受压力的能力不可避免地下降。目前尚不清楚压力信号机制本身效率的降低是否会导致这种与年龄相关的压力反应损伤。我们在剖析神经感觉系统向远端组织发出压力信号并非自主控制其反应的机制方面的专业知识为我们提供了解决这个问题的独特机会。假设：热感应诱导的 5-HT 释放会激活适应性细胞应激反应，从而保护蛋白质稳态。目标 1. 热感 (AFD) 神经元如何引发血清素能神经元释放 5-HT？目标 2. 5-HT 在反应性细胞中激活哪些组织间应激信号传导途径？