Mechanisms of renin-angiotensin signaling in programmed and insult-induced neuronal death

肾素-血管紧张素信号传导在程序性和损伤诱导的神经元死亡中的机制

• 批准号: 10297316
• 负责人: Su Guo
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-27 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297316
• 关键词: Address; Age; Aging; Angiotensin II; Angiotensins; Animal Model; Animals; Antibodies; Apoptosis; Basic Science; Blood Vessels; Brain; Brain Diseases; Cells; Chemicals; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Development; Diagnosis; Disease; Disease model; Dopamine; Drug usage; Etiology; Fishes; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Gaucher Disease; Genes; Genetic; Goals; Health; Human; Hypertension; Image; Immune; Impairment; In Situ; Injury; Invertebrates; Knock-out; Knowledge; Ligands; Metronidazole; Microglia; Microscopy; Modeling; Molecular; Molecular Genetics; Nerve Degeneration; Nervous System Physiology; Nervous system structure; Neurodegenerative Disorders; Neuroglia; Neurons; Neurosciences; Nitroreductases; Outcome; Parkinson Disease; Pathway interactions; Pattern; Peptidyl-Dipeptidase A; Process; Public Health; Reaction; Renin; Renin-Angiotensin System; Reporter; Research; Resolution; Rodent; Role; Signal Pathway; Signal Transduction; Sodium Chloride; Stains; Strategic Planning; System; Testing; Transgenic Organisms; United States National Institutes of Health; Vascular System; Vertebrates; Whole Organism; Zebrafish; base; blood pressure regulation; cell type; chemical genetics; dopaminergic neuron; glucosylceramidase; high throughput screening; imaging modality; in vivo; inhibitor/antagonist; insight; interest; men; microscopic imaging; neuron loss; neuropathology; receptor; relating to nervous system; small molecule; spatiotemporal; transcriptome sequencing

PROJECT SUMMARY An important goal in neuroscience is to elucidate with cellular and molecular clarity how neurodegeneration (ND) might occur in vivo, given the intricate signaling and interactions among neurons and glia in the brain. This application aims to understand a fundamental G Protein Coupled Receptor (GPCR) signaling pathway in both programmed neuronal death (PND) and insult-induced ND (IND). IND will be studied in in the context of Gaucher disease (GD), a multisystemic disorder including neuropathology before the age of three and Parkinson’s disease (PD). It is well known that neuronal death occurs both in development and in diseased conditions. During development, PND is critical for constructing a functional nervous system, e.g. by providing signals for the colonization of microglia. On the other hand, IND due to injury or disease processes significantly impairs the nervous system function. Studies employing invertebrate model organisms have provided insights. How PND and IND are mechanistically regulated in vertebrates, however, is not well understood. Through an unbiased whole organism-based small molecule screen employing a chemo-genetic nitroreductase/metronidazole (NTR/MTZ) dopamine (DA) neuron degeneration model in zebrafish, we have uncovered inhibitors of the renin-angiotensin system (RAS) that significantly protect neurons from both PND and IND. RAS is a peptidergic GPCR signaling system found in vertebrates, classically known to regulate blood pressure and salt retention. RAS inhibitors are widely used drugs for treating high blood pressure. The mechanism of action of RAS in ND however remains poorly understood, despite that RAS expression is detected in both neurons and glia, and altered expression is observed during aging, in multiple ND diseases, and inhibitors of RAS are in clinical trials for treating ND. We further find that inhibiting RAS signaling reduces DA ND in GD. Microglial colonization in the healthy developing brain is also significantly decreased upon RAS inhibition. Built on these preliminary data, we hypothesize that RAS signaling regulates both PND and IND outside its conventional role in the vascular system but involves neurons and glia. This hypothesis will be tested in both PND and IND, using a combination of molecular genetic, chemical genetic, and advanced microscopic imaging methods. Expected outcomes and impact: Through a systematic screen, we have uncovered a role of RAS signaling in both PND and IND in a highly accessible vertebrate model organism. The proposed research will create new fundamental knowledge to address the underlying mechanisms. Inhibitors of RAS signaling have clinical implications for treating ND diseases. By addressing the mechanisms of action for these agents, our research is well in line with NIH’s strategic plan to benefit human health through basic science research.

项目摘要 神经科学的一个重要目标是阐明神经变性（ND）的细胞和分子清晰度 鉴于大脑中神经元和神经胶质之间的复杂信号传导和相互作用，也许是体内。这 应用旨在了解两者中的基本G蛋白偶联受体（GPCR）信号通路 程序性神经元死亡（PND）和侮辱性诱导的ND（IND）。 IND将在Gaucher的背景下进行研究 疾病（GD），一种多系统疾病，包括三岁之前的神经病理学和帕金森氏病 疾病（PD）。 众所周知，神经元死亡既发生在发育和患病状况中。期间 开发，PND对于构建功能神经系统至关重要，例如通过提供信号 小胶质细胞的定殖。另一方面，由于受伤或疾病过程，IND极大地损害了 神经系统功能。采用无脊椎动物模型生物的研究提供了见解。如何PND 但是，在脊椎动物中机械调节IND并未得到很好的了解。 通过公正的整个生物体的小分子筛选，采用化学遗传 硝酸还原酶/甲硝唑（NTR/MTZ）多巴胺（DA）神经元变性模型在斑马鱼中，我们有 肾素 - 血管紧张素系统（RAS）的抑制剂显着保护神经元免受PND的侵害 和印度。 RAS是一种在脊椎动物中发现的Pepperidergic GPCR信号系统，通常已知可以调节血液 压力和盐的保留。 RAS抑制剂是广泛用于治疗高血压的药物。这 然而，ND中RAS的作用机理仍然鲜为人知，目的地是检测到RAS表达的目的地 在衰老期间，在多种ND疾病和抑制剂中都观察到神经元和神经元的表达改变。 Ras的治疗ND正在临床试验中。 我们进一步发现，抑制RAS信号会减少GD中的DA。健康的小胶质殖民化 在RAS抑制后，发育的大脑也大大减少。基于这些初步数据，我们 假设RAS信号传导在其在血管系统中的常规作用之外调节PND和IND 但涉及神经元和神经胶质。该假设将在PND和IND中进行检验，并使用 分子遗传，化学遗传和晚期微观成像方法。 预期的结果和影响：通过系统的屏幕，我们发现了RAS信号的作用 PND和IND都在高度可访问的脊椎动物模型生物体中。拟议的研究将创造新的 解决潜在机制的基本知识。 RAS信号的抑制剂具有临床 对治疗ND疾病的影响。通过解决这些代理的行动机制，我们的研究是 与NIH通过基础科学研究有益于人类健康的战略计划非常吻合。