The Function and Regulation of Tanycyte-Derived Hypothalamic Neurogenesis

单细胞来源的下丘脑神经发生的功能和调节

基本信息

批准号：
9181402
负责人：
Seth Blackshaw
金额：
$ 36.45万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9181402
关键词：
Address Adolescent Adult Affect Animals Behavioral Body Weight Body Weight decreased Cell Lineage Cells Ciliary Neurotrophic Factor Data Development Diet Fatty acid glycerol esters Gene Expression Gene Expression Profiling Generations Genetic Goals Half-Life High Fat Diet Histologic Hypothalamic structure IL6ST gene Individual Insulin Resistance Label Lead Leptin Leptin deficiency Leptin resistance Longevity Measures Metabolic syndrome Metabolism Molecular Morphology Mus Neurons Non-Insulin-Dependent Diabetes Mellitus Obesity Phenocopy Physiological Presynaptic Terminals Process Public Health Regulation Risk Factors Signal Transduction Source Stem cells Synapses Testing Visual Weight Gain cell type cytokine design diet and exercise experimental study genetic approach improved leptin receptor loss of function neural circuit neurogenesis newborn neuron novel therapeutics obesity management obesity treatment postnatal postsynaptic public health relevance receptor response tool

项目摘要

DESCRIPTION (provided by applicant): Obesity is the main risk factor for developing type II diabetes (T2D), a major and growing public health problem. Elevated adiposity leads to central leptin and insulin resistance, which in turn can trigger changes in homeostatic neural circuitry in the hypothalamus. This can ultimately lead to the development of metabolic syndrome and T2D. Neurogenesis in the adult hypothalamic parenchyma is disrupted by high fat diet (HFD) and leptin deficiency, leading to a reduction in the number of anorexigenic POMC- expressing neurons. We have recently identified hypothalamic tanycytes as a second source of newborn neurons in adult hypothalamus. Our preliminary data suggests that while HFD and leptin deficiency stimulate tanycyte-derived neurogenesis, tanycyte-derived neurons promote weight gain in wildtype animals but inhibit weight gain in leptin-deficient mice. The studies proposed here aim to improve our understanding of how tanycyte-derived neurons regulate body weight, and to determine how dietary signals regulate tanycyte-derived neurogenesis. First, using genetic approaches, we plan to investigate the physiological consequences of selectively disrupting and enhancing tanycyte-derived neurogenesis. Second, we plan to investigate the molecular mechanisms by which both HFD-induced cytokines such as CNTF and leptin regulate tanycyte-derived neurogenesis. Finally, we propose to determine the exact identity of tanycyte-derived neurons and to identify their post-synaptic targets. We anticipate that these studies will ultimately assist in the design of novel therapies for treatment of obesity and T2D.

描述（由应用程序提供）：肥胖是发展II型糖尿病（T2D）的主要危险因素，这是一个主要且日益严重的公共卫生问题。肥胖升高会导致中央瘦素和胰岛素抵抗，这反过来又会触发稳态神经回路的变化下丘脑。这最终可能导致代谢综合征和T2D的发展。成年下丘脑实质中的神经发生受高脂肪饮食（HFD）和瘦素缺乏症的破坏，导致厌食症POMC表达神经元的数量减少。我们最近将下丘脑tanycytes确定为成年下丘脑中新生神经元的第二个来源。我们的初步数据表明，虽然HFD和瘦素缺乏症刺激了tanycyte衍生的神经发生，但tanycyte衍生的神经元可促进野生型动物的体重增加，但抑制瘦素缺陷小鼠的体重增加。这里提出的研究旨在提高我们对丹尼纤维衍生的神经元如何调节体重的理解，并确定饮食信号如何调节tanycyteder的神经发生。首先，使用遗传方法，我们计划研究选择性破坏和增强tanycyte衍生的神经发生的物理后果。其次，我们计划研究HFD诱导的细胞因子（例如CNTF和瘦素调节）tanycyte衍生的神经发生的分子机制。最后，我们建议确定丹尼纤维衍生的神经元的确切身份，并确定其突触后靶标。我们预计，这些研究最终将有助于设计肥胖和T2D治疗的新型疗法。