Reprogramming organismal lifespan through modulation of neuropeptides

通过调节神经肽重新编程有机体寿命

• 批准号: 10507323
• 负责人: Claire Nicole Bedbrook
• 金额: $ 12.85万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10507323
• 关键词: Advisory Committees; African; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Animals; Arousal; Autopsy; Behavior; Behavioral; Biological Assay; Brain; Brain region; CRISPR/Cas technology; Cell Nucleus; Cells; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Cognition; Cognitive; Data; Disease; Energy Metabolism; Foundations; Galanin; Genes; Genetic; Genetic Screening; Goals; Health; Homeostasis; Human; Hypothalamic structure; Impaired cognition; In Situ; Inflammation; Institution; Killifishes; Knock-in; Knock-out; Label; Laboratories; Libraries; Life; Longevity; Measurement; Measures; Mediating; Memory Loss; Mentors; Methods; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuromedin U; Neuromodulator; Neurons; Neuropeptides; Neurosciences; Pathway interactions; Pattern; Peptides; Phenotype; Physiological; Pigmentation physiologic function; Protocols documentation; Regulation; Research; Risk Factors; Role; Signaling Molecule; Sleep; Technology; Testing; Training; Transcript; Transgenic Animals; Transgenic Organisms; Translating; Universities; Vertebrates; Work; career development; experimental study; feeding; gene discovery; healthspan; hypocretin; knockout animal; mouse model; mutant; neuromedin U receptor; novel; overexpression; pituitary adenylate cyclase activating polypeptide; prevent; programs; receptor; screening; skills; tool; β-amyloid burden

Aging is the primary risk factor for debilitating diseases such as Alzheimer’s disease. Can manipulation of neurons in the brain alter the body’s physiological state to extend lifespan and prevent neurodegenerative disease? Neuropeptides are signaling molecules released by neurons that act through modulatory receptors expressed throughout the brain and body to regulate homeostasis. Whether neuropeptides could control long-term phenotypes such as the rate of aging, neurodegeneration and cognitive decline remains largely unknown. Neuropeptides have been implicated in Alzheimer’s disease in humans. For example, the neuropeptide Galanin (GAL) is overexpressed in degenerating brain regions in Alzheimer’s disease, low levels of the neuropeptide Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) are correlated with higher amyloid burden and memory decline, and the number of neurons expressing the neuropeptide Hypocretin are significantly reduced in postmortem hypothalamus of Alzheimer's disease patients. However, a systematic characterization of the role and mode of action of neuropeptides in regulating vertebrate lifespan and their impact on neurodegeneration and cognitive decline is missing. This is largely because aging and lifespan experiments in transgenic vertebrates are slow (3+ years in mice) and low throughput. I will take advantage of a short-lived vertebrate model the African killifish to (1) determine if deletion of key neuropeptides can alter lifespan, healthspan, and cognitive decline, (2) investigate the mode of action of one neuropeptide that I have already found to extend lifespan when knocked out, and (3) test if neuropeptides can act as pro-longevity factors when delivered later in life to counter age-associated cognitive decline. To achieve this, I will use interdisciplinary technologies at the nexus of genetics, aging, and neuroscience. I already have exciting tools and data that support my goal. I built a library of neuropeptide knockout killifish targeting 22 human-conserved neuropeptides using CRISPR/Cas9 and I optimized the protocol for lifespan and healthspan assessment in the killifish. In tantalizing preliminary data, I found that knockout of the AD-associated neuropeptide GAL in killifish results in progressive cognitive decline suggesting that neuropeptides could be key modulators of neurodegeneration in disease such as Alzheimer’s disease. By focusing on diverse neuropeptides that interact with specific druggable receptors, I hope the long-term impact of this work will translate to clinical solutions to age-associated Alzheimer’s disease and others. For the mentored part of my training at Stanford University, I will receive training from my mentor Dr. Karl Deisseroth, co-mentor Dr. Anne Brunet, and an exceptional scientific advisory team with expertise in neuroscience, neuropeptides, aging, neurodegeneration, genetic screening, and CRISPR methods. This work, my technical training, and my career development at Stanford University will provide me with the skills and foundations required to be a leader of a laboratory at a top academic institution, discovering genes critical for longevity and for countering cognitive decline in Alzheimer’s disease.

衰老是阿尔茨海默病等衰弱性疾病的主要危险因素。控制大脑中的神经元是否可以改变身体的生理状态以延长寿命并预防神经退行性疾病？神经肽是神经元释放的信号分子，通过整个大脑表达的调节受体发挥作用。神经肽是否可以控制衰老速度、神经退行性变和认知能力下降等长期表型，目前仍不清楚神经肽是否与阿尔茨海默病有关。例如，人类的神经肽甘丙肽（GAL）在阿尔茨海默病的退化大脑区域中过度表达，神经肽垂体腺苷酸环化酶激活多肽（PACAP）的低水平与较高的淀粉样蛋白负担和记忆力下降以及神经元数量相关。阿尔茨海默氏病患者死后下丘脑中神经肽下丘脑的表达显着减少，但神经肽的作用和系统作用模式的表征。调节脊椎动物寿命及其对神经退行性变和认知能力下降的影响缺失，这主要是因为转基因脊椎动物的衰老和寿命实验缓慢（在小鼠中进行了 3 年以上）并且我将利用寿命较短的脊椎动物模型。非洲鳉鱼（1）确定关键神经肽的缺失是否会改变寿命、健康状况和认知能力下降，（2）研究我已经发现的一种神经肽的作用模式（3）测试神经肽在晚年交付时是否可以作为延长寿命的因素，以对抗与年龄相关的认知能力下降。为了实现这一目标，我将在遗传学、衰老、我已经有了令人兴奋的工具和数据来支持我的目标，我使用 CRISPR/Cas9 构建了一个针对 22 种人类保守神经肽的神经肽敲除鳉鱼库，并优化了协议的寿命和寿命。在诱人的初步数据中，我发现敲除鳉鱼中与 AD 相关的神经肽 GAL 会导致认知能力逐渐下降，这表明神经肽可能是阿尔茨海默病等疾病的神经退行性疾病的关键调节剂。与特定的可药物受体相互作用，我希望这项工作的长期影响能够转化为与年龄相关的阿尔茨海默病和其他疾病的临床解决方案，以用于我在斯坦福大学培训的指导部分。大学期间，我将接受我的导师 Karl Deisseroth 博士、联合导师 Anne Brunet 博士以及一支杰出的科学顾问团队的培训，他们在神经科学、神经肽、衰老、神经退行性疾病、基因筛查和 CRISPR 方法方面拥有专业知识。技术培训和我在斯坦福大学的职业发展将为我提供成为顶级学术机构实验室领导者所需的技能和基础，发现对长寿和对抗阿尔茨海默病认知能力下降至关重要的基因。