Development and function of Crhbp+ neurons in the zebrafish hypothalamus

斑马鱼下丘脑 Crhbp 神经元的发育和功能

基本信息

批准号：
10611936
负责人：
Priscilla Figueroa
金额：
$ 3.82万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10611936
关键词：
Ablation Affect Anxiety Area Behavior Behavioral Biological Assay Biological Models Brain C-terminal CRISPR/Cas technology Cell Transplantation Cells Chimera organism Cognition Communication Darkness Data Development Disease Diving Embryo Endocrine Enzyme-Linked Immunosorbent Assay Exhibits Exons Exploratory Behavior Frameshift Mutation Future Gastrula Gene Expression Regulation Generations Genes Genetic Genetic Transcription Goals Homeostasis Hormones Human Hydrocortisone Hypothalamic structure Individual Investigation Knock-out Larva Link Measures Mediating Mediator Mental Depression Mentors Messenger RNA Metronidazole Molecular Mood Disorders Moods Mus Mutation Names Neurons Nitroreductases Pathway interactions Peripheral Phenotype Physiology Pituitary Gland Play Population Posterior Hypothalamus Procedures Protein Isoforms RNA Splicing Recovery Regulation Reporter Research Research Personnel Research Proposals Role Scientist Series Signal Pathway Stress Tail Testing Tissues Training Transgenes Transgenic Organisms Transplantation Vertebrates Work Zebrafish beta catenin biological adaptation to stress blastomere structure career corticotropin releasing factor-binding protein embryo cell experimental study mutant neurogenesis neuron development neuronal circuitry neuropsychiatric disorder novel overexpression response skills student mentoring training opportunity transcription factor transcriptome sequencing

项目摘要

Project Summary/Abstract The vertebrate hypothalamus maintains physiological homeostasis through regulation of the stress response pathway. Disruption of this pathway can lead to neuropsychiatric disorders, but many of the genes and neurons involved are unidentified. Our lab has discovered that the Wnt pathway mediator Lef1 regulates hypothalamic neurogenesis and stress-related exploratory behavior, and my preliminary data suggest that a specific Lef1 protein isoform enriched in the developing brain may play a unique role in both of these functions. The development of hypothalamic neurons expressing corticotropin-releasing hormone binding protein (Crhbp) depends on Lef1 as well as its transcriptional target otbp, providing a hypothesized mechanism linking Wnt- dependent transcription to behavior. This research proposal will test this hypothesis while providing technical and career training essential for my goal to become an independent academic researcher. In my first Aim I will create mutations disrupting specific Lef1 isoforms, and assess their effects on hypothalamic neurogenesis, physiology, and behavior. In my second Aim, I will use cell transplantation to create genetic chimeras, and determine whether Crhbp+ cells are necessary and sufficient to regulate exploratory behavior downstream of Lef1 and Otpb. From this project I will identify molecules and circuits that may be conserved between zebrafish and human stress response pathways, and gain new skills that will allow me to become a successful scientist and mentor.

项目概要/摘要脊椎动物下丘脑通过调节应激反应维持生理稳态途径。该通路的破坏可能导致神经精神疾病，但许多基因和神经元涉案人员身份不明。我们实验室发现Wnt通路介质Lef1调节下丘脑神经发生和压力相关的探索行为，我的初步数据表明特定的 Lef1 发育中的大脑中富含的蛋白质亚型可能在这两种功能中发挥独特的作用。这表达促肾上腺皮质激素释放激素结合蛋白（Crhbp）的下丘脑神经元的发育依赖于 Lef1 及其转录靶点 otbp，提供了一种连接 Wnt-的假设机制行为的依赖转录。本研究计划将检验这一假设，同时提供技术支持职业培训对于我成为一名独立学术研究员的目标至关重要。在我的第一个目标中我会创建破坏特定 Lef1 同工型的突变，并评估它们对下丘脑神经发生的影响，生理学和行为。在我的第二个目标中，我将使用细胞移植来创造基因嵌合体，并且确定 Crhbp+ 细胞是否必要且足以调节下游的探索行为 Lef1 和 Otpb。从这个项目中，我将识别斑马鱼之间可能保守的分子和电路和人类压力反应途径，并获得新技能，使我成为一名成功的科学家和导师。