TLX Ligands in Neural Stem Cells & Neurodegeneration

描述（由申请人提供）：孤儿核受体TLX在成年哺乳动物大脑中表达，对维持神经干细胞的增殖状态至关重要。TLX基因敲除小鼠在成年大脑的神经发生区显示出细胞增殖受损和神经祖细胞减少。本研究的目的是利用新型亲和/GC-MS技术鉴定中枢神经系统中的内源性TLX配体，并利用基于细胞的检测方法通过化学文库筛选鉴定合成TLX配体。这些配体将被用作研究神经干细胞自我更新的工具，并为控制神经干细胞增殖和分化的分子机制提供见解。我们还将进行初步实验，在神经退行性动物模型中测试这些小分子对干细胞繁殖和神经元再生的影响，以确定它们是否是改善神经退行性疾病的潜在药理工具。最终，这些小分子将作为治疗神经退行性疾病（如阿尔茨海默病）的潜在治疗配体进行测试。这些研究将整合各种跨学科的方法，并在两个独立的小组之间充分合作。每个小组将为项目贡献独特但互补的专业知识和资源。这些研究结果将为TLX配体的本质及其功能如何与神经干细胞自我更新和神经发生相关提供独特的见解。因此，这些研究直接响应了NINDS干细胞生物学合作研究。

DESCRIPTION (provided by applicant): Orphan nuclear receptor TLX is expressed in adult mammalian brains and critical in maintaining the proliferative state of neural stem cells. TLX knockout mice display impaired cell proliferation and reduced neural progenitors in neurogenic areas of adult brains. The objective of this study is to identify endogenous TLX ligands in the central nervous system using novel affinity/GC-MS technology and identify synthetic TLX ligands by chemical library screening using cell-based assays. These ligands will be used as tools to study neural stem cell self-renewal and to provide insights into the molecular mechanisms that control neural stem cell proliferation and differentiation. We will also perform preliminary experiments to test the effects of these small molecules on stem cell propagation and neuronal regeneration in neurodegenerative animal models to determine if they are potential pharmacological tools for the improvement of neurodegenerative diseases. Ultimately, these small molecules will be tested as potential therapeutical ligands for the treatment of neurodegenerative diseases such as Alzheimer's disease. These studies will integrate a variety of interdisciplinary approaches and engage full collaborations between two independent groups. Each group will contribute unique yet complementary expertise and resources to the project. Results from these studies will provide unique insights into the nature of TLX ligands and how their functions are related to neural stem cell self-renewal and neurogenesis. Thus, these studies are directly responsive to the NINDS Collaborative Research in Stem Cell Biology.