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.

衰老是使阿尔茨海默氏病等疾病使人衰弱的主要危险因素。对大脑中神经元的操纵是否可以改变人体的身体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，这些分子在整个大脑和身体表达以调节稳态的整个调节受体作用。神经肽是否可以控制长期表型，例如衰老率，神经退行性和认知下降的速度仍然很大未知。在人类的阿尔茨海默氏病中，神经肽已隐含。例如，在阿尔茨海默氏病的退化大脑区域中，神经肽葡萄蛋白（GAL）过表达，低水平的神经肽垂体腺苷酸环化酶环化蛋白活化多肽（PACAP）与较高的疗程和肿瘤的数量相关，并在表达较高的神经抑制性刺激性的数量阿尔茨海默氏病患者。但是，缺少神经肽在确定脊椎动物寿命及其对神经变性和认知下降的影响的系统表征。这主要是因为转基因脊椎动物的衰老和寿命实验慢（小鼠3年以上）和低吞吐量。 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认知能力下降。为了实现这一目标，我将在遗传学，衰老和神经科学的联系中使用跨学科技术。我已经有了支持我目标的激动人心的工具和数据。我使用CRISPR/CAS9建立了一个神经肽敲除Killifish的杀伤力，靶向22种人类保存的神经肽，并在Killifish中优化了寿命和健康范围评估的方案。在诱人的初步数据中，我发现在促进性认知下降中与AD相关的神经肽GAL的敲除表明神经肽可能是阿尔茨海默氏病等疾病中神经变性的关键调节剂。通过专注于与特定可药物接收器相互作用的潜水神经肽，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氏病等临床解决方案。对于我在斯坦福大学进行培训的部分培训，我将获得我的心理Karl Deisseroth博士，同事Anne Brunet博士的培训，以及一个具有神经科学，神经肽，衰老，神经变性，神经变性，基因筛查和CRISPR方法的专业知识的杰出科学咨询团队。这项工作，我的技术培训以及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金会，发现对长寿至关重要的基因以及反对阿尔茨海默氏病认知能力下降的基因。