Hippocampal regulation and neuroprotection by NPC-derived VEGF

描述(申请人提供)：干细胞疗法在治疗人类疾病，特别是目前无法治愈的神经退行性疾病方面大有可为。然而，为了有效地利用干细胞的治愈潜力，有必要了解这些细胞如何与环境相互作用并对其做出反应。在移植中，干细胞可以作为替代细胞，对局部提示做出反应，帮助修复受损组织。它们也可以作为保护性信号的来源，在其未分化的状态下分泌促进局部修复过程的生长因子。这项提议关注的是干细胞作为神经调节分泌细胞的第二个鲜为人知的角色。这项建议的目的是研究成年神经干细胞/祖细胞(NPC)来源的海马区分泌物的调节和神经保护作用。鉴于在几种神经退行性疾病中，如颞叶癫痫和阿尔茨海默病，海马体的显著退化，这一大脑区域为干细胞治疗提供了一个有吸引力的靶点。Wyss-Coray实验室之前已经证明，分离的成年海马神经干细胞大量分泌各种生长因子，其中最著名的是高度神经保护的血管内皮生长因子(VEGF)。我的目标是研究鼻咽癌来源的血管内皮细胞生长因子调节海马体功能并提供神经保护以防止退行性疾病的假说。在目标1中，我将利用针对鼻咽癌的基因敲除技术，确定鼻咽癌来源的血管内皮生长因子如何在体外和体内调节其他鼻咽癌细胞的增殖和分化。在目标2中，我将使用来自目标1的体内基因敲除模型来确定鼻咽癌来源的血管内皮生长因子如何调节成年小鼠的局部血管环境和海马区行为。最后，在目标3中，我将在神经损伤的兴奋性毒性模型中测试来自内源性鼻咽癌(和鼻咽癌移植)的鼻咽癌来源的血管内皮生长因子的神经保护作用。这些研究将有助于对鼻咽癌如何在体内作为未来的治疗方法提供关键的理解。这个项目结合了基础神经科学和翻译研究，要求我精通一门广泛的技能。 准备好了。我将在鼻咽癌体外培养、shRNA、lox-cre遗传学、海马体立体定向注射和疾病的神经退行性模型方面获得经验。通过这个项目，我的目标是获得旨在寻求神经退行性疾病治疗的翻译研究方面的专业知识。

DESCRIPTION (provided by applicant): Stem cell therapies hold great promise for treatment of human disease, particularly for currently incurable neurodegenerative diseases. However, to effectively harness the healing potential of stem cells, it is necessary to understand how these cells interact with and respond to their environment. In transplants, stem cells may function as replacement cells that respond to local cues to help mend damaged tissue. They may also function as a source of protective cues, secreting in their undifferentiated state growth factors that facilitate local repair processes. This proposal focuses on this second, less well understood role of stem cells as neuromodulatory secretory cells. The goal of this proposal is to investigate the regulatory and neuroprotective role of adult neural stem/progenitor cell (NPC)-derived secretions in the hippocampus. Given the prominent degradation of the hippocampus in several neurodegenerative disorders such as temporal lobe epilepsy and Alzheimer's disease, this brain area provides an attractive target for stem cell therapy. The Wyss-Coray lab has previously shown that isolated adult hippocampal NPCs secrete a variety of growth factors in large quantities, most notably the highly neuroprotective vascular endothelial growth factor (VEGF). My goal is to investigate the hypothesis that NPC- derived VEGF regulates hippocampal function and provides neuroprotection from degenerative disease. In Aim 1, I will determine how NPC-derived VEGF regulates the proliferation and differentiation of other NPCs in vitro and in vivo using genetic knockdown techniques specific to NPCs. In Aim 2, I will use the in vivo knockdown models from Aim 1 to determine how NPC- derived VEGF regulates the local vascular environment and hippocampal behavior in adult mice. Finally, in Aim 3, I will test the neuroprotective qualities of NPC-derived VEGF from endogenous NPCs (and from NPC transplants) in an excitotoxic model of neural insult. These studies will help provide critical understanding of how NPCs may function as future therapies in vivo. This project combines basic neuroscience with translational research, requiring that I become proficient in a broad skill set. I will gain experience in in vitro NPC culture, shRNA, lox- cre genetics, stereotaxic injectios into the hippocampus and neurodegenerative models of disease. Through this project, it is my goal to acquire expertise in translational research designed to pursue treatment for neurodegenerative disease.