In Vivo Control and Functional Visualization of Stem Cell-Driven CNS Regeneration

描述(由申请人提供) 摘要：这项建议建议将遗传学、干细胞生物学和功能磁共振成像(FMRI)中的大胆新概念结合起来，以解决一个以前从未被开发过的单一问题：我们能否在体内直接绘制干细胞驱动的神经回路再生的功能图？尽管中枢神经系统(CNS)疾病的衰弱特征和治疗开发的紧迫性，但脊髓损伤、帕金森氏病、阿尔茨海默病、多发性硬化症和中风等中枢神经系统疾病潜在的复杂神经结构本质上否定了它们迄今可行的治疗方法。在这里，干细胞再生未分裂细胞的基本能力，以及诱导多能干细胞(IPSC)的最新发展，为一类全新的创新治疗提供了新的动力，在这些治疗中，受损的神经电路可能会通过干细胞诱导的神经发生部分或完全恢复。我们试图通过引入一种全新的方法来直接评估体内干细胞驱动的神经电路的功能，从而在这一关键努力中发挥作用。这将通过结合基因技术来实现，这些基因技术将根据神经细胞的细胞类型向其引入调节和/或报告能力。我们将战略性地将病毒载体引入潜在的神经回路以及移植的干细胞。对于干细胞转染，我们希望我们提出的技术只允许那些发育成特定细胞类型的细胞具有调节/报告能力。这种特定于细胞的调制/报告能力将与一种新的无失真功能磁共振成像技术相结合，允许对再生过程进行非侵入性和高分辨率的可视化。该项目一旦成功，将为体内再生的神经组织提供直接的功能评估能力。这反过来将为开发治疗中枢神经系统疾病的新型干细胞疗法提供关键指导。 与公共卫生相关：神经回路的复杂性和功能特性使脊髓损伤、帕金森氏病、阿尔茨海默病、多发性硬化症和中风等中枢神经系统(CNS)疾病对治疗方法特别具有挑战性。虽然最近诱导多能干细胞(IPSC)的发展为衰弱的中枢神经系统疾病患者提供了全新的创新治疗方案，但干细胞诱导中枢神经系统再生的最终功能仍然难以捉摸。该项目一旦成功，将为体内再生的神经组织提供直接的功能评估能力。这反过来将为开发治疗中枢神经系统疾病的新型干细胞疗法提供关键指导。

DESCRIPTION (Provided by the applicant) Abstract: This proposal suggests a consilience of bold new concepts in genetics, stem cell biology, and functional magnetic resonance imaging (fMRI) to address a singular question that could never be tapped previously: can we directly map the functionality of stem cell-driven neural circuit regeneration in vivo? Despite the debilitating character of central nervous system (CNS) diseases, and the urgency for therapeutic development, the complex nature of the neural fabric underlying CNS diseases such as spinal cord injuries, Parkinson's disease, Alzheimer's disease, multiple sclerosis, and stroke, substantially negate their viable cure to date. Here, the fundamental ability of stem cells to regenerate non-dividing cells, as well as recent development of induced pluripotent stem cells (IPSC) gives fresh impetus for a whole new class of innovative treatments where damaged neural circuitry might be partially or fully restored by stem-cell induced neurogenesis. We seek to be instrumental in this pivotal endeavor by introducing a completely novel way of directly assessing the functionality of stem cell driven neural circuitry in vivo. This will be achieved by combining genetic techniques that will introduce modulatory and/or reporting capability to neural cells based on its cell type. We will strategically introduce viral vectors to both the underlying neural circuit as well as transplanted stem cells. For stem cell transfection, we expect our proposed technique to allow modulatory/reporting capability from only those developing into specific cell types. This cell-specific modulation/reporting capability will then combined with a novel distortion-free fMRI imaging technique, permitting non-invasive and high-resolution visualization of the regeneration processes. This project, upon its success, will provide direct functional assessment capabilities for the regenerated nerve tissue in vivo. This in turn will provide key guidance for developing novel stem cell therapies for CNS diseases. Public Health Relevance: The complexity and functional nature of neural circuitry makes central nervous systems (CNS) diseases such as spinal cord injuries, Parkinson's disease, Alzheimer's disease, multiple sclerosis, and stroke particularly challenging for therapeutic approaches. While recent development of induced pluripotent stem cells (IPSC) gives fresh impetus for a whole new class of innovative treatment landscapes for patients with debilitating CNS diseases, the ultimate functionality of stem cell induced CNS regeneration remains elusive. This project, upon its success, will provide direct and functional assessment capabilities for the regenerated nerve tissue in vivo. This in turn will provide key guidance for developing novel stem cell therapies for CNS diseases.