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: 10434599
• 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/10434599
• 关键词: Age; Aging; Alzheimer' s Disease; Animals; Brain; Cell Aging; 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; 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.

项目总结 年龄是大多数慢性人类疾病的主要风险因素，包括阿尔茨海默病(AD)。神经 干细胞(NSCs)特别容易受到细胞老化的影响，并在成熟时经历功能衰退。 大脑。结果，成年神经发生及其对健康和AD患者记忆的贡献受到损害 很小的时候。再生医学治疗阿尔茨海默病的中心目标是确定使人返老还童的因素 内源性神经干细胞和增强认知。然而，NSCs通常被认为是一个糟糕的反 老龄化干预。NSC复兴仍然面临着一个艰巨的挑战：恢复较老的NSC增殖， 增加神经干细胞的数量，改变神经发生的命运，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种潜在的解决方案。我们建议 开发计算网络和药物基因组学方法，优先考虑和调整与年龄相关的关键因素 NSC年轻化的变化。我们之前的工作利用单细胞转录来定义分子级联 启动成人神经发生，并在衰老过程中受到损害。初步数据现在确定了一个新的 区分静态和活动NSC的过渡签名，并随时间变化。我们的新单细胞 药物基因组学方法利用过渡信号来确定一种使神经干细胞恢复活力的化合物 通过扩大神经干细胞池、增加神经发生和维持神经干细胞增殖来发挥作用。动物 行为学研究还表明，老年小鼠的认知能力有所改善。因此，本提案中详细说明的数据 强烈建议我们可以应用组合的“组学”方法对较旧的NSC功能进行重新编程，并提供 对成人衰老过程中神经发生的新认识。调节NSC重新编程的机制 仍然是个谜。我们将利用系统生物学技术在网络上推进新的药物基因组学 连接性和共同表达，以确定逆转NSC老化的优先机制(目标1)，较旧的NSC 扩大功能(目标2)以及如何维持这些变化(目标3)。 总而言之，这项研究将揭示NSC复兴的证据，并证明 新的单细胞药物基因组学和促进老年海马区神经发生的基因网络。 这些结果将提供NSC再生能力的范式转变，以及机械论的洞察力 转化为NSC对衰老的脆弱性，对其衰退的韧性，并建立认知储备。