Nutrient sensing ghrelin signaling - a novel pathogenic factor for Alzheimer’s Disease

项目摘要 补充依据：本申请是对NOT-AG-20-034的回应， 该组织呼吁对阿尔茨海默病（AD）进行新的研究。我的国家投资局基金 （1 R 01 AG 064869），标题为“巨噬细胞重编程和炎症中的营养感测GHS-R”。 老化”，2019年7月1日至2024年4月30日，不以AD为重点。它研究了生长激素释放肽受体GHS- 衰老过程中肝脏和脂肪组织中巨噬细胞重编程中的R，重点是免疫 外周组织的代谢调节。衰老与代谢下降有关， 全身炎症加剧新的证据表明，神经炎症 在AD的发病机制中起重要作用。在本补充中，我们的目的是研究GHS-R在以下方面的作用： AD中小胶质细胞的代谢重编程。这种补充提供了一种新的免疫代谢 角度AD领域，揭示了一个新的作用GHS-R在AD。我们认为这 补充是在一般范围内的资助R 01，但扩展到一个令人兴奋的新的 这是与NIA资助的赠款互补和协同作用的AD方面。 补充资料的范围：我们已经报告了GHS-R的整体消融改善了 老化代谢和减轻全身炎症老化，显示抗炎 巨噬细胞极化。小胶质细胞是神经炎症的主要驱动因素，我们的初步研究表明， 数据显示，AD引发的内毒素显著增加了小胶质细胞中GHS-R的表达 脂多糖（LPS）和GHS-R拮抗剂抑制LPS诱导的炎症， 巨胶质细胞。我们假设GHS-R是AD的致病因子，GHS-R促进促肾上腺皮质激素释放， 小胶质细胞的炎症激活和极化加剧了 AD.我们将通过以下方法研究小胶质细胞GHS-R缺陷型5XFAD小鼠（Cx 3cr 1CreER;Ghsrflox/flox; 5XFAD） 具体目标：目标1。确定小胶质细胞GHS-R对学习和 记忆、神经炎症和AD病理学。目标二。确定偏振状态， AD中GHS-R缺陷型小胶质细胞的细胞/分子特征和调节机制。 补充资金的影响：这笔补充资金将为我们提供更多- 需要支持来研究我们的新假设我们独特的小鼠模型和坚实的初步 数据结合我们在免疫学和衰老代谢方面的专业知识， 成功的前提和高可行性。我们有信心成功完成 在该奖项的支持下进行研究。目前提案的结果将为 对于AD中营养物感应GHS-R的进一步机制研究的成熟项目， 这有可能导致新的免疫干预AD。

Project Summary Justification of the supplement: This application is in response to NOT-AG-20-034, which calls new research initiatives on Alzheimer's disease (AD). My funded NIA grant (1R01AG064869), entitled “Nutrient-sensing GHS-R in macrophage reprogramming and inflamm- aging”, 7/1/2019- 4/30/2024, is not AD-focused. It investigates the roles of ghrelin receptor GHS- R in macrophage reprogramming in liver and adipose tissues during aging, focusing on immuno- metabolic regulation in peripheral tissues. Aging is associated with metabolic decline and increased inflammation throughout the body. Emerging evidence shows that neuroinflammation has major roles in pathogenesis of AD. In this supplement, we aim to study the role of GHS-R in metabolic reprogramming of microglia in AD. This supplement provides a new immuno-metabolic angle to the AD field, shedding light on a novel role of GHS-R in AD. We believe that this supplement is within the general scope of the funded R01, but expands into an exciting new aspect of AD which is both complementary and synergistic with the NIA funded grant. Scope of the supplement: We have reported that global ablation of GHS-R improves aging metabolism and mitigates systemic inflammation in aging, showing anti-inflammatory macrophage polarization. Microglia are the primary drivers of neuroinflammation, our preliminary data showed that GHS-R expression in microglia is drastically increased by AD-priming endotoxin lipopolysaccharides (LPS) and GHS-R antagonist suppresses LPS-induced inflammation in macroglia. We hypothesize that GHS-R is a pathogenic factor for AD; GHS-R promotes pro- inflammatory activation and polarization of microglia to exacerbate neuroinflammation in AD. We will study microglial GHS-R deficient 5XFAD mice (Cx3cr1CreER;Ghsrflox/flox; 5XFAD) via the following Specific Aims: Aim 1. Determine the role of microglial GHS-R on learning and memory, neuroinflammation, and AD pathology. Aim 2. Determine the polarization state, cellular/molecular signatures, and regulatory mechanisms of GHS-R deficient microglia in AD. The impact of the supplement: This supplemental funding will provide us with the much- needed support to investigate our new hypothesis. Our unique mouse model and solid preliminary data combined with our expertise in immunology and aging metabolism offer strong scientific premise and high feasibility for success. We are confident that we will successfully complete the proposed studies with the support of the award. Results from current proposal will set the stage for a full-fledged project in further mechanistic investigation of nutrient–sensing GHS-R in AD, which has potential to lead to novel immunotherapeutic interventions for AD.