TLX Ligands in Neural Stem Cells & Neurodegeneration

描述(申请人提供)：孤儿核受体TLX在成年哺乳动物脑中表达，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源性区域表现出细胞增殖受损和神经前体细胞减少。本研究的目的是利用新的亲和/GC-MS技术鉴定中枢神经系统中的内源性TLX配体，并通过基于细胞的化学文库筛选来鉴定合成的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，以测试这些小分子在神经退行性动物模型中对干细胞增殖和神经元再生的影响，以确定它们是否为改善神经退行性疾病的潜在药理学工具。最终，这些小分子将被测试为治疗阿尔茨海默病等神经退行性疾病的潜在治疗配体。这些研究将整合各种跨学科的方法，并在两个独立小组之间进行充分的合作。每个小组都将为该项目贡献独特而互补的专门知识和资源。这些研究的结果将为TLX配体的性质以及它们的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.