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.

衰老是导致老年痴呆症等衰弱性疾病的主要危险因素。操纵大脑中的神经元是否可以改变身体的生理状态，从而延长寿命并预防神经退行性疾病？神经肽是由神经元释放的信号分子，其通过在整个大脑和身体中表达的调节受体起作用以调节稳态。神经肽是否可以控制长期的表型，如衰老，神经退行性变和认知能力下降的速度仍然是未知的。神经肽与人类阿尔茨海默病有关。例如，神经肽甘丙肽（GAL）在阿尔茨海默病的退化脑区域中过表达，低水平的神经肽腺苷酸环化酶激活多肽（PACAP）与较高的淀粉样蛋白负荷和记忆力下降相关，并且在阿尔茨海默病患者的死后下丘脑中表达神经肽下丘脑泌素的神经元的数量显著减少。然而，神经肽在调节脊椎动物寿命中的作用和作用模式及其对神经退行性变和认知能力下降的影响的系统表征缺失。这在很大程度上是因为转基因脊椎动物的衰老和寿命实验是缓慢的（在小鼠中为3年以上）和低通量的。我将利用一种短寿命的脊椎动物模型--非洲鳉鱼来（1）确定关键神经肽的缺失是否会改变寿命、健康寿命和认知能力下降，（2）研究一种神经肽的作用模式，我已经发现这种神经肽在被敲除时可以延长寿命，以及（3）测试神经肽在生命后期传递时是否可以作为促长寿因子，以对抗与年龄相关的认知衰退。为了实现这一目标，我将在遗传学，衰老和神经科学的关系中使用跨学科技术。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建立了一个神经肽敲除的鳉鱼库，靶向22种人类保守的神经肽，并优化了鳉鱼寿命和健康评估的方案。在诱人的初步数据中，我发现在鳉鱼中敲除AD相关的神经肽GAL会导致进行性认知下降，这表明神经肽可能是阿尔茨海默病等疾病中神经退行性变的关键调节剂。通过专注于与特定药物受体相互作用的各种神经肽，我希望这项工作的长期影响将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。对于我在斯坦福大学培训的指导部分，我将接受我的导师Karl Deisseroth博士，共同导师Anne Brunet博士以及一个在神经科学，神经肽，衰老，神经变性，遗传筛查和CRISPR方法方面具有专业知识的杰出科学顾问团队的培训。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。