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疾病的主要危险因素。操纵大脑中的神经元能改变身体的生理状态以延长寿命并预防神经退行性疾病吗？神经肽是神经元释放的信号分子，通过表达在大脑和身体各处的调制受体来调节体内平衡。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，目前还很大程度上尚不清楚。神经肽被认为与人类的阿尔茨海默病有关。例如，神经肽Galanin(GAL)在阿尔茨海默病患者退行性脑区域过度表达，神经肽垂体腺苷环化酶激活多肽(PACAP)水平低与淀粉样蛋白负荷较高和记忆力下降相关，阿尔茨海默病患者死后下丘脑中表达神经肽下丘脑的神经元数量显著减少。然而，神经肽在调节脊椎动物寿命中的作用和作用方式以及它们对神经退化和认知衰退的影响还缺乏系统的表征。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缓慢(在小鼠身上为3年以上)和低吞吐量。我将利用一个短暂的脊椎动物模型--非洲千里鱼--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)研究我已经发现的一种神经肽在被敲除时延长寿命的作用模式，以及(3)测试神经肽在晚年使用时是否可以作为促长寿因素来对抗与年龄相关的认知能力下降。为了实现这一点，我将在遗传学、衰老和神经科学的结合点上使用跨学科技术。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建立了一个针对22个人类保守神经肽的神经肽敲除小鱼文库，并对小鱼的寿命和健康寿命评估方案进行了优化。在诱人的初步数据中，我发现在千里鱼中敲除与AD相关的神经肽GAL会导致进行性认知能力下降，这表明神经肽可能是阿尔茨海默病等疾病中神经退化的关键调节因素。通过专注于与特定可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。在斯坦福大学的培训中，我将接受我的导师Karl Deisseroth博士、共同导师Anne Brunet博士的培训，以及一个出色的科学顾问团队，他们拥有神经科学、神经肽、衰老、神经变性、基因筛查和CRISPR方法方面的专业知识。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所需的技能和基础，使我能够成为一所顶尖学术机构的实验室负责人，发现对长寿和对抗阿尔茨海默病认知衰退至关重要的基因。