Intrinsic and Extrinsic factors regulating neurogenic competence in hypothalamic tanycytes

调节下丘脑单细胞神经源能力的内在和外在因素

基本信息

批准号：
10828978
负责人：
Leighton Hosea Duncan
金额：
$ 4.87万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-14 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10828978
关键词：
Ablation Acute Adolescent Adult Affect Apoptotic Award Biology Body Weight Cell Death Cell physiology Cells Competence Data Development Disease Educational workshop Family Funding Gene Expression Gene Expression Profile Generations Genetic Models Genomics Hypothalamic structure Injections Injury Institution Intrinsic factor Knowledge Mechanics Mediating Metabolic Metabolic Diseases Metabolism Modeling Molecular Morphology Mus Natural regeneration Nerve Regeneration Neuroglia Neurons Non-Insulin-Dependent Diabetes Mellitus Obesity Phase Principal Investigator Proliferating Radial Repression Research Rest Retina Role SOX8 gene Signal Transduction Surgical Models Tamoxifen Techniques Telencephalon Testing Therapeutic Training Virus Zebrafish career career development cell regeneration cell type cold blooded vertebrate differential expression gene regulatory network genetic approach insulinoma associated 1 mature animal multiple omics nerve stem cell neural neurogenesis notch protein nuclear factor 1 overexpression post-doctoral training postnatal postnatal development pre-doctoral single-cell RNA sequencing stem symposium transcription factor transcriptomics young adult

项目摘要

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.

下丘脑单细胞具有有限的出生后神经源能力，但外在和内在的促进这一现象的因素尚不清楚。我的博士前研究确定了一个明确的发展下丘脑单细胞丧失神经源能力的窗口。我还确定了神经源性 bHLH 转录因子 Ascl1 作为单细胞神经源性能力的候选激活剂并发现 Shh 信号传导可能促进单细胞衍生神经元的存活。 F99阶段在这个奖项中，我将研究 AAV 介导的 Ascl1 过度表达是否会诱导神经源性能力以及Shh信号是否通过细胞特异性促进单细胞衍生神经元的存活条件遗传方法。在K00阶段，我将进行以斑马鱼为对象的博士后培训识别控制损伤引起的下丘脑神经再生的基因调控网络的模型，识别尚未表征的调节神经源能力的外在和内在机制 tanycyte样放射状胶质细胞。通过将这些发现与从哺乳动物单细胞获得的数据进行比较，我计划识别神经源能力的正向和负向调节因子，可以操纵这些因子来诱导单细胞衍生的特定下丘脑神经元细胞类型的产生，用于治疗代谢和其他体内平衡紊乱。这些机会将促进我作为神经科学家的职业生涯并为我做好准备担任 R1 机构的首席研究员，研究单细胞生物学和下丘脑再生。