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 补充的理由：此申请是响应于20-034的响应 称阿尔茨海默氏病（AD）的新研究计划。我资助的Nia Grant （1R01AG064869），标题为“巨噬细胞重编程中的营养感应GHS-R 衰老”，7/1/2019-4/30/2024，没有被定位。 在衰老期间，巨噬细胞重新编程的巨噬细胞重编程，重点是免疫 周围组织中的代谢调节。衰老与代谢下降和 整个身体的炎症增加。新兴证据表明神经炎症 在AD的发病机理中具有重要作用。在这种补充中，我们旨在研究GHS-R在 AD中小胶质细胞的代谢重编程。该补充剂提供了一种新的免疫代谢 与广告领域的角度，阐明了GHS-R在AD中的新作用。我们相信这个 补充剂在资助R01的一般范围内，但扩展为令人兴奋的新的 与NIA资助的赠款既完整又协同的广告方面。 补充的范围：我们报告说，GHS-R的全球消融有所改善 衰老的代谢和减轻衰老的全身性炎症，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 数据表明，通过广告蛋白质内毒素，小胶质细胞中的GHS-R表达大大增加 脂多糖（LPS）和GHS-R拮抗剂抑制了LPS诱导的炎症 大元。我们假设GHS-R是AD的致病因素。 GHS-R促进了Pro- 小胶质细胞的炎症激活和极化，以加剧神经炎症的神经炎症 广告。我们将通过研究小胶质ghs-r缺乏5xFAD小鼠（CX3CR1CREER； GHSRFLOX/FLOX; 5XFAD） 以下具体目的：目标1。确定小胶质ghs-r在学习和 记忆，神经炎症和AD病理学。目标2。确定极化状态， AD中GHS-R缺乏小胶质细胞的细胞/分子特征和调节机制。 补充的影响：这种补充资金将为我们提供很多 需要支持以研究我们的新假设。我们独特的鼠标模型和固体初步 数据结合我们的免疫学和衰老代谢方面的专业知识提供了强大的科学 前提和成功的可行性。我们相信我们将成功完成 在奖项的支持下提议的研究。当前建议的结果将设定舞台 对于全面的项目，以进一步研究AD中的营养 - 传感GHS-R 这有可能导致新的AD免疫治疗干预措施。