Hippocampal regulation and neuroprotection by NPC-derived VEGF

描述（由申请人提供）：干细胞疗法对治疗人类疾病，特别是目前无法治愈的神经退行性疾病有很大的希望。然而，为了有效地利用干细胞的愈合潜力，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，对局部信号做出反应，帮助修复受损组织。它们也可以作为保护性信号的来源，在未分化状态下分泌促进局部修复过程的生长因子。这个建议集中在第二个，不太清楚的干细胞作为神经调节分泌细胞的作用。本研究的目的是探讨成人神经干/祖细胞（NPC）来源的分泌物在海马中的调节和神经保护作用。鉴于海马体在几种神经退行性疾病如颞叶癫痫和阿尔茨海默病中的显著退化，该脑区为干细胞治疗提供了有吸引力的靶点。Wyss-Coray实验室先前已经表明，分离的成年海马NPC大量分泌各种生长因子，最值得注意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VEGF调节海马功能并提供神经保护以防止退行性疾病的假设。在目的1中，我将确定如何NPC衍生的VEGF调节其他NPC的增殖和分化在体外和体内使用特定的NPC基因敲除技术。在目标2中，我将使用目标1中的体内敲低模型来确定NPC衍生的VEGF如何调节成年小鼠的局部血管环境和海马行为。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NPC（和来自NPC移植物）的NPC衍生的VEGF的神经保护性质。这些研究将有助于提供关键的理解如何NPC可能作为未来的治疗在体内发挥作用。这个项目结合了基础神经科学和转化研究，要求我精通一项广泛的技能 集我将在体外NPC培养、shRNA、lox-cre遗传学、海马立体定位注射和神经退行性疾病模型方面获得经验。通过这个项目，我的目标是获得旨在寻求治疗神经退行性疾病的转化研究的专业知识。

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.