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

项目总结 神经科学的一个重要目标是在细胞和分子水平上阐明神经退行性变(ND)是如何发生的。 可能发生在体内，因为大脑中神经元和胶质细胞之间的信号和相互作用错综复杂。这 应用目的是了解两种疾病的基本G蛋白偶联受体(GPCR)信号通路 程序性神经元死亡(PND)和损伤性ND(IND)。IND将在Gaucher的背景下进行研究 疾病(GD)，一种多系统疾病，包括三岁前的神经病理学和帕金森氏症 疾病(PD)。 众所周知，神经元死亡既发生在发育中，也发生在疾病条件下。在.期间 发展，PND对于构建功能神经系统至关重要，例如通过为 小胶质细胞定植。另一方面，由于受伤或疾病过程而导致的IND显著损害了 神经系统功能。使用无脊椎动物模型生物的研究提供了洞察力。如何PND 和IND在脊椎动物中是机械调节的，然而，还不是很清楚。 通过基于整个生物体的无偏见的小分子筛查，采用化学遗传学 在斑马鱼的硝基还原酶/甲硝唑(NTR/MTZ)多巴胺(DA)神经元变性模型中，我们有 未发现的肾素-血管紧张素系统(RAS)抑制剂可显著保护神经元免受PND的影响 和Ind.RAS是在脊椎动物中发现的一种肽能gpr信号系统，经典地认为它可以调节血液。 压力和盐分滞留。RAS抑制剂是广泛用于治疗高血压的药物。这个 然而，尽管检测到RAS的表达，但RAS在ND中的作用机制仍然知之甚少 在神经元和神经胶质细胞中，在多种ND疾病和抑制剂中，在衰老过程中观察到表达的变化 正在进行治疗新城疫的临床试验。 我们进一步发现，抑制RAS信号通路降低了GD患者的DA-ND。健康人小胶质细胞定植的研究 RAS抑制后，大脑发育也明显减少。基于这些初步数据，我们 假设RAS信号对PND和IND的调节超出其在血管系统中的常规作用 但涉及神经元和神经胶质细胞。这一假设将在PND和IND中进行测试，使用以下组合 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信号在 PND和IND都在一个高度可及的脊椎动物模式生物中。拟议的研究将创造新的 基础知识，以解决潜在的机制。RAS信号转导抑制剂具有临床应用价值 对新城疫治疗的启示。通过解决这些制剂的作用机制，我们的研究是 这符合美国国立卫生研究院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.