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

• 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
• 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

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.

下丘脑伸长细胞具有有限的生后神经原性能力，但其外在和内在的神经原性能力是有限的。 促进这一点的因素尚未得到很好的理解。我的博士前研究确定了一个明确的发展 下丘脑伸长细胞丧失神经原性能力的窗口期。我还确定了 神经源性bHLH转录因子Ascl1作为伸长细胞神经源性能力的候选激活因子 并确定Shh信号可能促进伸长细胞衍生神经元的存活。在F99阶段 在这个奖项中，我将研究AAV介导的Ascl1过表达是否诱导神经原性 能力以及Shh信号是否促进了使用细胞特异性 条件遗传学方法在K00阶段，我将继续使用斑马鱼作为博士后培训。 模型来识别控制损伤诱导的下丘脑神经再生的基因调控网络， 确定尚未表征的调节神经原性能力的外在和内在机制， 伸展细胞样放射状胶质细胞。通过将这些发现与从哺乳动物伸长细胞获得的数据进行比较，我计划 确定神经原性能力的正性和负性调节因子， 用于治疗代谢性和神经性疾病的特异性下丘脑神经元细胞类型的伸长细胞衍生的产生 其他稳态失调。这些机会将推动我作为一名神经科学家的职业生涯， 在R1研究所担任首席研究员，研究伸展细胞生物学和下丘脑再生。