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

营养感应生长素释放肽信号——阿尔茨海默病的一种新致病因素

• 批准号: 10285433
• 负责人: YUXIANG SUN
• 金额: $ 37.88万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285433
• 关键词: Ablation; Adipose tissue; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Anti-Inflammatory Agents; Attenuated; Award; Biological Response Modifiers; Blood; Brain; Cell Lineage; Complement; Data; Disease Marker; Endotoxins; Exhibits; Flow Cytometry; Funding; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Genus Hippocampus; Goals; Grant; High Fat Diet; Hormones; Immunology; Immunotherapeutic agent; Immunotherapy; Impaired cognition; Inflammaging; Inflammation; Inflammatory; Injury; Insulin Resistance; Intervention; Investigation; Knowledge; Lead; Learning; Light; Lipopolysaccharides; Liver; M cell; Mediating; Memory; Metabolic; Metabolism; Microglia; Molecular; Molecular Profiling; Mus; Myeloid Cells; Neurodegenerative Disorders; Neurons; Obesity; Pathogenesis; Pathogenicity; Pathway Analysis; Peripheral; Play; Prognosis; Regulation; Reporting; Research; Resources; Rest; Rodent; Role; Senile Plaques; Signal Pathway; Signal Transduction; Solid; Testing; Time; Tissues; Virulence Factors; base; cognitive function; cognitive testing; cytokine; detection of nutrient; diet-induced obesity; feeding; ghrelin; ghrelin receptor; growth hormone secretagogue receptor; improved; macroglia; macrophage; monocyte; mouse model; neuroinflammation; neuropathology; novel; object recognition; receptor expression; response; spatial memory; success; systemic inflammatory response

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.

项目摘要 补充理由：本申请是对NOT-AG-20-034的回应， 它呼吁对阿尔茨海默病(AD)的新的研究倡议。我资助的NIA基金 (1R01AG064869)，标题为“巨噬细胞重编程和炎症中的营养感测GHS-R- 老龄化“，2019年7月1日至2024年4月30日，不以AD为重点。它研究了Ghrelin受体GHS-的作用。 R在衰老过程中肝脏和脂肪组织中巨噬细胞的重新编程，重点是免疫- 外周组织的代谢调节。衰老与新陈代谢下降和 全身炎症加剧。新出现的证据表明，神经炎症 在AD的发病机制中起着重要作用。在本补充材料中，我们旨在研究GHS-R在 阿尔茨海默病小胶质细胞的代谢重编程。这种补充剂提供了一种新的免疫代谢 角度到AD领域，揭示了GHS-R在AD中的新角色。我们相信这一点 补充是在资助的R01的一般范围内，但扩展为一个令人兴奋的新 AD方面，与国家投资局资助的赠款相辅相成，并具有协同作用。 补充范围：我们已经报告了GHS-R的全球消融改善 衰老代谢，减轻衰老过程中的全身炎症，显示抗炎作用 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 研究表明，AD诱导的内毒素可显著增加小胶质细胞GHS-R的表达 脂多糖和GHS-R拮抗剂抑制内毒素诱导的炎症反应 大胶质细胞。我们推测GHS-R是AD的致病因素；GHS-R促进了前-GHS-R的功能。 小胶质细胞的炎性激活和极化加剧神经炎症 广告。我们将通过以下方式研究小胶质细胞GHS-R缺陷的5XFAD小鼠(Cx3cr1Creer；Ghsrflx/Flox；5XFAD) 目的1.确定小胶质细胞GHS-R在学习和发育中的作用 记忆、神经炎症和AD病理。目标2.确定偏振态， 阿尔茨海默病患者GHS-R缺陷小胶质细胞的细胞/分子特征及其调控机制。 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说。我们独特的老鼠模型和坚实的初步 结合我们在免疫学和衰老新陈代谢方面的专业知识，数据提供了强有力的科学依据 成功的前提和高度的可行性。我们有信心我们将成功地完成 在该奖项的支持下提出的研究。当前提案的结果将奠定基础 对于在AD中进一步进行营养传感GHS-R机制研究的成熟项目， 这有可能导致AD的新的免疫治疗干预措施。