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: 10836739
• 负责人: Kelly Rich
• 金额: $ 7.6万
• 依托单位: HARVARD MEDICAL SCHOOL
• 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 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10836739
• 关键词: Cellular; reprogramming; promote; longevity; resilience

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.

项目总结/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。 时序老化是神经退行性变的既定风险因素，并导致功能障碍和神经元的丧失。 运动单位（MU;运动神经元及其支配的所有肌纤维）。此外，遗传变异可能会加速 生物老化和获得性神经系统细胞损伤。然而，衰老的哺乳动物组织 表观遗传特征，最近的出版物强调了细胞重编程等策略，以恢复 年轻的组织弹性。我的长期职业目标是获得一个终身制临床科学家的位置， 学术机构，并建立一个翻译研究计划。这样的职位将使我能够实现我的 长期的科学目标是研究遗传易感性背景下神经系统的细胞衰老。 我的短期科学目标和这个建议的基础是测试假设， 衰老途径独立，并与疾病特异性基因疗法相结合，可能提供一个有前途的 开发针对神经变性的新治疗策略的途径。我的博士项目研究 Kinesin-1 Family Member 5A（KIF 5A）是一种已知的神经退行性疾病易感基因 肌萎缩侧索硬化症（ALS）。突变型Kif 5a小鼠在损伤的情况下表现出功能性MU的丧失 和衰老，与可观察到的病理学相关。这些数据支持KIF 5A在MU中的突出作用。 这表明突变的KIF 5A无法对抗生物挑战，如损伤或年龄。F99 该奖项的第一阶段将测试ALS相关Kif 5a突变导致单倍不足的假设， 使用病毒载体来操纵Kif 5a表达。K 00阶段将建立在我的经验与MU 生理学、病理学和病毒载体来更广泛地研究衰老和神经退行性变。作为博士后，我会 研究疾病的生理触发因素（基因组和染色体组），生物衰老， 和表型。具体来说，拟议的工作将研究AAV介导的细胞重编程， 转录因子Oct 4，Sox 2和Klf 4来改善MU寿命，恢复力和修复，然后将其应用于 遗传性MU疾病的方法。目的2A将测试个体的诱导的瞬时重编程的效果。 MU细胞类型对功能、表观遗传、转录组和组织病理学结局的影响。目标2B将调查 当面对MU损伤时，细胞重编程在增强老年MU修复和恢复力方面的价值。 目的2C将测试多转基因递送促进长寿的细胞重编程的效用 独立地和与现有的基因疗法结合以对疾病表型具有协同作用。 这些研究将提供有关MU寿命，恢复力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。此外该 拟议的职业发展计划是经过深思熟虑的设计，以发展技术专长，科学 沟通技巧和指导经验是成为独立调查员所必需的。