Intrinsic and Extrinsic factors regulating neurogenic competence in hypothalamic tanycytes

下丘脑张力细胞在出生后具有有限的神经生成能力，但外源性和内在的 推动这一点的因素还没有得到很好的理解。我的博士前研究发现了一种明确的发育 在此期间，下丘脑柔韧细胞的神经源性能力丧失。我还确定了 神经源性bHLH转录因子Ascl1作为柔韧细胞神经源性能力的候选激活剂 并发现Shh信号潜在地促进了Tanycell来源的神经元的存活。在F99阶段 在这个奖项中，我将调查AAV介导的Ascl1过表达是否诱导神经源性 能力和Shh信号是否通过细胞特异性促进Tanycell来源神经元的存活 有条件的遗传方法。在K00阶段，我将继续使用斑马鱼进行博士后培训 识别控制损伤诱导的下丘脑神经再生的基因调控网络的模型， 识别尚未确定的调节神经源性能力的外在和内在机制 松弛细胞样放射状神经胶质细胞。通过将这些发现与从哺乳动物松弛细胞中获得的数据进行比较，我计划 找出神经源性能力的积极和消极调节因素，可以被操纵来诱导 Tanycell来源的特定下丘脑神经细胞类型的产生用于治疗代谢和 其他动态平衡紊乱。这些机会将推动我作为一名神经学家的职业生涯，并为我做好准备 在一家研究松弛细胞生物学和下丘脑再生的R1机构担任首席研究员一职。

Hypothalamic tanycytes have limited postnatal neurogenic competence, but the extrinsic and intrinsic factors that promote this are not well understood. My predoctoral research identified a defined developmental window during which neurogenic competence is lost from hypothalamic tanycytes. I have also identified the neurogenic bHLH transcription factor Ascl1 as a candidate activator of neurogenic competence in tanycytes and identified Shh signaling as potentially promoting the survival of tanycyte-derived neurons. In the F99 phase of this award, I will investigate whether AAV-mediated overexpression of Ascl1 induces neurogenic competence and whether Shh signaling promotes the survival of tanycyte-derived neurons using cell-specific conditional genetic approaches. During the K00 phase, I will pursue postdoctoral training using zebrafish as a model to identify gene regulatory networks controlling injury-induced hypothalamic neural regeneration, identifying yet uncharacterized extrinsic and intrinsic mechanisms that regulate neurogenic competence in tanycyte-like radial glial cells. By comparing these findings to data obtained from mammalian tanycytes, I plan to identify both positive and negative regulators of neurogenic competence that could be manipulated to induce the tanycyte-derived generation of specific hypothalamic neuronal cell types for treatment of metabolic and other homeostatic disorders. These opportunities will advance my career as a neuroscientist and prepare me for a principal investigator role at an R1 institution studying tanycyte biology and hypothalamic regeneration.