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.

项目概要 补充的理由：本申请是为了回应 NOT-AG-20-034， 这就是我资助的 NIA 资助的关于阿尔茨海默病 (AD) 的新研究计划。 (1R01AG064869)，标题为“巨噬细胞重编程和炎症中的营养感应 GHS-R” 衰老”，7/1/2019-4/30/2024，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重编程中的作用，重点关注免疫 外周组织的代谢调节与代谢下降有关。 新的证据表明，神经炎症增加。 在本补充品中，我们旨在研究 GHS-R 在 AD 发病机制中的作用。 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。 从 AD 领域的角度出发，揭示了 GHS-R 在 AD 中的新作用。 补充在资助的 R01 的一般范围内，但扩展到一个令人兴奋的新 AD 方面与 NIA 资助的赠款既互补又协同。 补充范围：我们报告了 GHS-R 的全球消融改善 衰老代谢并减轻衰老过程中的全身炎症，表现出抗炎作用 我们初步认为，巨噬细胞极化是神经炎症的主要驱动因素。 数据显示，AD 引发的内毒素可显着增加小胶质细胞中的 GHS-R 表达 脂多糖 (LPS) 和 GHS-R 拮抗剂可抑制 LPS 诱导的炎症 我们认为 GHS-R 是 AD 的致病因子； 小胶质细胞的炎症激活和极化加剧神经炎症 AD. 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;Ghsrflox/flox; 5XFAD) 具体目标如下： 目标 1. 确定小胶质细胞 GHS-R 对学习和学习的作用 记忆、神经炎症和 AD 病理学 目标 2. 确定极化状态， AD 中 GHS-R 缺陷小胶质细胞的细胞/分子特征和调节机制。 补充资金的影响：这项补充资金将为我们提供更多- 我们独特的小鼠模型和可靠的初步研究需要支持来研究我们的新假设。 数据与我们在免疫学和衰老代谢方面的专业知识相结合，提供了强有力的科学依据 我们有信心成功完成这一任务。 在该奖项的支持下提出的研究将奠定基础。 对于 AD 中营养感应 GHS-R 的进一步机制研究的成熟项目， 这有可能为 AD 带来新的免疫治疗干预措施。