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

项目概要 神经科学的一个重要目标是通过细胞和分子的清晰度阐明神经退行性变 (ND) 是如何发生的 鉴于大脑中神经元和神经胶质细胞之间复杂的信号传导和相互作用，这种情况可能发生在体内。这个 应用程序旨在了解基本的 G 蛋白偶联受体 (GPCR) 信号通路 程序性神经元死亡（PND）和损伤诱导的神经元死亡（IND）。 IND 将在 Gaucher 的背景下进行研究 疾病（GD），一种多系统疾病，包括三岁前的神经病理学和帕金森病 疾病（PD）。 众所周知，神经元死亡发生在发育过程中和患病情况下。期间 PND 对于构建功能性神经系统（例如神经系统）至关重要。通过提供信号 小胶质细胞的定植。另一方面，由于损伤或疾病过程而引起的 IND 会严重损害 神经系统功能。使用无脊椎动物模式生物的研究提供了见解。如何进行PND IND 和 IND 在脊椎动物中受到机械调节，但尚不清楚。 通过采用化学遗传学的无偏见的基于整个生物体的小分子筛选 斑马鱼硝基还原酶/甲硝唑（NTR/MTZ）多巴胺（DA）神经元变性模型，我们有 发现肾素-血管紧张素系统 (RAS) 抑制剂可显着保护神经元免受 PND 的影响 和IND。 RAS 是在脊椎动物中发现的肽能 GPCR 信号系统，传统上已知可调节血液 压力和盐潴留。 RAS抑制剂是广泛用于治疗高血压的药物。的 然而，尽管检测到了 RAS 表达，但对 ND 中 RAS 的作用机制仍知之甚少 在神经元和神经胶质细胞中，在衰老过程中、在多种 ND 疾病和抑制剂中观察到表达改变 RAS 正在进行治疗 ND 的临床试验。 我们进一步发现抑制 RAS 信号传导可减少 GD 中的 DA ND。健康人体内的小胶质细胞定植 抑制 RAS 后，大脑发育也会显着下降。根据这些初步数据，我们 假设 RAS 信号传导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细胞。该假设将在 PND 和 IND 中进行检验，结合使用 分子遗传学、化学遗传学和先进的显微成像方法。 预期结果和影响：通过系统筛选，我们发现了 RAS 信号传导在 PND 和 IND 在易于获取的脊椎动物模型生物中。拟议的研究将创造新的 解决基本机制的基础知识。 RAS信号抑制剂具有临床应用价值 对治疗 ND 疾病的影响。通过解决这些药物的作用机制，我们的研究是 非常符合NIH通过基础科学研究造福人类健康的战略计划。

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.