Cellular reprogramming to promote longevity, resilience, and repair in motor unit degeneration

细胞重编程可促进长寿、恢复能力和运动单位退化的修复

• 批准号: 10562291
• 负责人: Kelly Rich
• 金额: $ 4.27万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2023-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10562291
• 关键词: Adult; Age; Aging; Amyotrophic Lateral Sclerosis; Award; Biological; Biological Aging; Cell Aging; Chronology; Clinical; Communication; Data; Development; Development Plans; Disease; Electrophysiology (science); Epigenetic Process; Family member; Foundations; Functional disorder; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genome; Goals; Individual; Injury; Institution; Kinesin; Knowledge; Lead; Link; Longevity; Maintenance; Mediating; Mentorship; Motivation; Motor; Motor Neurons; Mus; Muscle Fibers; Mutant Strains Mice; Mutation; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Peripheral nerve injury; Phase; Phenotype; Physiological; Physiology; Population; Positioning Attribute; Postdoctoral Fellow; Process; Proteins; Publications; Research; Research Personnel; Research Project Grants; Risk Factors; Role; Science; Scientist; Susceptibility Gene; Technical Expertise; Testing; Therapeutic; Tissues; Viral Vector; Work; age related; age related neurodegeneration; aged; career; career development; cell injury; cell type; clinically relevant; combat; design; disease phenotype; effective therapy; experience; functional loss; gene therapy; genetic variant; improved; in vivo; interest; mouse model; mutant; neurogenetics; neuromuscular; neuromuscular function; neuronal transport; novel therapeutic intervention; pathological aging; pre-doctoral; repaired; resilience; senescence; skills; tenure track; therapy development; transcription factor; transcriptional reprogramming; transcriptomics; transgene delivery; translational research program; treatment strategy

PROJECT SUMMARY/ABSTRACT The global population is aging rapidly – the number of adults over 65 is expected to double by 2050. Chronological aging is an established risk factor for neurodegeneration and leads to dysfunction and loss of the motor unit (MU; a motor neuron and all the myofibers it innervates). Further, genetic variants may accelerate biological aging and acquired cellular damage in the nervous system. However, aged mammalian tissues retain an epigenetic signature, and recent publications highlight strategies such as cellular reprogramming to restore youthful tissue resilience. My long-term career goal is to obtain a tenure-track clinician-scientist position at an academic institution and establish a translational research program. Such a position will allow me to achieve my long-term scientific goal to investigate cellular aging of the nervous system in the setting of genetic predisposition. My short-term scientific goal and the foundation of this proposal is to test the hypothesis that targeting biological aging pathways independently and in conjunction with disease-specific gene therapies may provide a promising avenue to develop new therapeutic strategies targeting neurodegeneration. My doctoral project investigates Kinesin-1 Family Member 5A (KIF5A), a known susceptibility gene for the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Mutant Kif5a mice demonstrate loss of functional MUs in the context of injury and aging, with observable pathological correlates. These data support a prominent role of KIF5A in MU maintenance, suggesting mutant KIF5A is unable to combat biological challenges such as injury or age. The F99 phase of this award will test the hypothesis that ALS-associated Kif5a mutations lead to haploinsufficiency and use viral vectors to manipulate Kif5a expression. The K00 phase will build upon my experience with MU physiology, pathology and viral vectors to study aging and neurodegeneration more broadly. As a postdoc, I will study the interdependence between physiological triggers of disease (genome and exposome), biological aging, and phenotype. Specifically, the proposed work will investigate AAV-mediated cellular reprogramming of transcription factors Oct4, Sox2, and Klf4 to improve MU longevity, resilience and repair, and then apply this approach to genetic MU disease. Aim 2A will test the effect of induced, transient reprogramming of individual MU cell types on functional, epigenetic, transcriptomic, and histopathological outcomes. Aim 2B will investigate the value of cellular reprogramming in enhancing aged MU repair and resilience when faced with MU insults. Aim 2C will test the utility of multi-transgene delivery of longevity-promoting cellular reprogramming independently and in conjunction with existing gene therapies to have a synergistic effect on disease phenotype. These studies will provide critical information about mechanisms of MU longevity, resilience and repair and will test a therapeutic approach that has implications for all age-related neurodegenerative diseases. In addition, the proposed career development plan was thoughtfully designed to develop the technical expertise, science communication skills, and mentorship experience essential to becoming an independent investigator.

项目摘要/摘要 全球人口正在迅速老龄化--预计到2050年，65岁以上的成年人数量将翻一番。 慢性衰老是神经退行性变的既定危险因素，并导致功能障碍和 运动单位(MU；运动神经元及其支配的所有肌纤维)。此外，基因变异可能会加速 神经系统的生物老化和获得性细胞损伤。然而，老化的哺乳动物组织保留了 一种表观遗传特征，最近的出版物强调了一些策略，如细胞重新编程来恢复 年轻的组织弹性。我的长期职业目标是获得一个终身教职的临床医生兼科学家的职位 学术机构，并建立翻译研究计划。这样的职位将使我能够实现我的目标 长期科学目标是在遗传易感性的背景下研究神经系统的细胞老化。 我的短期科学目标和这一提议的基础是测试以生物为目标的假设 衰老途径独立并与疾病特异性基因治疗相结合可能提供一种有希望的 开发针对神经退行性变的新治疗策略。我的博士项目调查 激动素-1家族成员5A(KIF5A)，已知的神经退行性疾病的易感基因 肌萎缩侧索硬化症(ALS)。Kif5a突变小鼠在损伤背景下表现出功能性MU的丧失 和衰老，与可观察到的病理相关。这些数据支持KIF5A在MU中的突出作用 维护，这表明突变的KIF5A无法应对伤害或年龄等生物挑战。F99 该奖项的阶段将检验ALS相关Kif5a突变导致单倍体功能不全和 使用病毒载体操纵Kif5a表达。K00阶段将建立在我与MU的经验基础上 生理学、病理学和病毒载体，以更广泛地研究衰老和神经退化。作为博士后，我会 研究疾病的生理诱因(基因组和曝光组)、生物衰老、 和表型。具体地说，拟议的工作将研究AAV介导的细胞重新编程 转录因子Oct4、Sox2和Klf4，以提高MU的寿命、弹性和修复能力，然后应用此 探讨遗传性MU病。目标2A将测试诱导的、瞬时的重新编程对个体的影响 MU细胞类型对功能、表观遗传学、转录和组织病理学结果的影响。AIM 2B将进行调查 细胞重编程在增强老年MU修复和面对MU侮辱时的恢复能力方面的价值。 目标2C将测试多转基因传递促进长寿细胞重新编程的效用 独立和与现有的基因疗法一起对疾病表型产生协同效应。 这些研究将提供有关MU寿命、韧性和修复机制的关键信息，并将 测试一种对所有与年龄相关的神经退行性疾病都有影响的治疗方法。此外， 提出的职业发展计划是经过深思熟虑的，旨在发展技术专长、科学知识 沟通技巧，以及成为一名独立调查员所必需的指导经验。