Neural stem cell rejuvenation through single cell pharmacogenomics

通过单细胞药物基因组学恢复神经干细胞活力

• 批准号: 10636910
• 负责人: MICHAEL Bonaguidi
• 金额: $ 76.68万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636910
• 关键词: Age; Aging; Alzheimer' s Disease; Animals; Brain; Cell Aging; Cell Reprogramming; Cells; Chronic; Cognition; Country; Data; Goals; Government Agencies; Health; Institution; Intervention; Legal; Mediating; Memory; Molecular; Monitor; Mus; Names; Pharmacogenomics; Procedures; Regenerative Medicine; Regenerative capacity; Rejuvenation; Research; Resources; Risk Factors; Security; Societies; Systems Biology; Techniques; Work; adult neurogenesis; age related; aging hippocampus; anti aging; behavioral study; cognitive reserve; gene network; human disease; improved; insight; nerve stem cell; neurogenesis; novel strategies; performance site; programs; resilience; stem cell aging; stem cell fate; stem cell function; stem cell proliferation; transcriptomics

PROJECT SUMMARY Age is the major risk factor for most chronic human diseases, including Alzheimer’s disease (AD). Neural stem cells (NSCs) are particularly vulnerable to cellular aging and undergo functional decay in the mature brain. As a result, adult neurogenesis and its contributions to memory in health and AD are compromised at early ages. A central goal in regenerative medicine for AD is to determine the factors that rejuvenate endogenous NSCs and augment cognition. Yet, NSCs are commonly perceived to be a poor target for anti- aging interventions. A daunting challenge remains for NSC rejuvenation: to restore older NSC proliferation, increase their numbers, alter NSC fate for neurogenesis and sustain these changes. Systems biology offers a potential solution by integrating information from multiple fields. We propose to develop computational network and pharmacogenomics approaches to prioritize and modulate key age-related changes for NSC rejuvenation. Our prior work utilized single cell transcriptomics to define molecular cascades that initiate adult neurogenesis and are compromised during aging. Preliminary data now identifies a new transition signature that distinguishes quiescent from active NSCs and is altered with age. Our new single cell pharmacogenomics approach utilizes the transition signature to identify a compound that rejuvenates NSC function by expanding the NSC pool, increasing neurogenesis and sustaining NSC proliferation. Animal behavioral studies also demonstrate improved cognition in older mice. Thus, data detailed in this proposal strongly suggests we can apply combined “omics” approaches to reprogram older NSC function and provide a new understanding of adult neurogenesis in aging. The mechanisms mediating this NSC reprogramming remain enigmatic. We will advance the new pharmacogenomics with systems biology techniques in network connectivity and co-expression to prioritize mechanisms by which NSC aging is reversed (Aim 1), older NSC function is augmented (Aim 2) and how these changes are sustained (Aim 3). Together, this study will reveal evidence of NSC rejuvenation and demonstrate proof-of-principle utility of new single cell pharmacogenomics and gene networks for enhancing neurogenesis in the aged hippocampus. These results would provide a paradigm shift in NSC capacity for regeneration, as well as mechanistic insight into NSC vulnerability to aging, resilience to their decline, and building cognitive reserve.

项目摘要 年龄是大多数慢性人类疾病的主要危险因素，包括阿尔茨海默病（AD）。神经 干细胞（NSC）特别容易受到细胞老化的影响，并且在成熟的细胞中经历功能衰退。 个脑袋因此，成年神经发生及其对健康和AD记忆的贡献在以下情况下受到损害： 早期AD再生医学的一个中心目标是确定使AD恢复活力的因素。 内源性神经干细胞和增强认知。然而，神经干细胞通常被认为是抗肿瘤的不良靶点。 老龄化干预。国家安全委员会的复兴仍然面临着一个艰巨的挑战：恢复旧的国家安全委员会的扩散， 增加它们的数量，改变NSC的神经发生命运并维持这些变化。 系统生物学通过整合来自多个领域的信息提供了一个潜在的解决方案。我们建议 开发计算网络和药物基因组学方法，以优先考虑和调节关键的年龄相关的 NSC更新的变化。我们先前的工作利用单细胞转录组学来定义分子级联 启动成年神经发生并在衰老过程中受损。初步数据现在确定了一个新的 转换签名区分静止和活跃的神经干细胞，并随着年龄的变化。我们的新单细胞 药物基因组学方法利用转换签名来鉴定使NSC恢复活力的化合物 通过扩大NSC库、增加神经发生和维持NSC增殖来发挥功能。动物 行为研究也证明老年小鼠的认知能力得到了改善。因此，本提案中详细说明的数据 这强烈表明，我们可以应用组合的"组学"方法来重新编程较老的NSC功能，并提供一种新的治疗方法。 对衰老过程中成人神经发生的新认识。介导这种NSC重新编程的机制 仍然是个谜我们将以系统生物学技术为基础，以网络为平台，推进新的药物基因组学研究 连接和共表达，以优先考虑NSC老化逆转的机制（目标1），老年NSC 功能增强（目标2）以及这些变化如何持续（目标3）。 总之，这项研究将揭示NSC年轻化的证据，并证明 新的单细胞药物基因组学和基因网络，用于增强老年海马神经发生。 这些结果将为NSC的再生能力提供一个范式转变， NSC对衰老的脆弱性，对衰退的恢复力，以及建立认知储备。