Development of Hypothalamic Neurons That Control Energy Balance

控制能量平衡的下丘脑神经元的发育

基本信息

批准号：
8926986
负责人：
JAE W LEE
金额：
$ 58.48万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8926986
关键词：
Address Adult Affect Behavioral Binding Biochemical Genetics Body Size Brain Brain region Cells Cessation of life ChIP-seq Congenital Abnormality Defect Development Diabetes Mellitus Disease Embryo Embryonic Development Endocrine Energy Metabolism Equilibrium Family Feeding behaviors Gene Expression Profile Gene Targeting Genes Genetic Markers Health Heart Homeostasis Hormonal Hypothalamic structure Immunohistochemistry In Situ Hybridization Islet Cell Islets of Langerhans Knockout Mice Melanocyte stimulating hormone Metabolic Metabolic syndrome Molecular Motor Neurons Mus Mutant Strains Mice Nervous system structure Neuraxis Neurons Obesity Organ Pancreas Pathway interactions Pattern Peptides Phenotype Play Pro-Opiomelanocortin Process Regulator Genes Reporting Role Seminal Sequence Analysis Signal Transduction Societies Specific qualifier value Spinal Spinal Cord Staging Structure of nucleus infundibularis hypothalami Testing Time Up-Regulation base cell type cohort detection of nutrient energy balance feeding genome-wide homeodomain in vivo islet member mouse model mutant neuropeptide Y pandemic disease postnatal transcription factor transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): The hypothalamus plays critical roles in homeostasis and energy metabolism, and thus defects in hypothalamic development result in serious pathological conditions, including diabetes and obesity (1). However, how the diverse array of hypothalamic cell types is specified and organized remains poorly defined, partly due to the anatomical complexity of this essential brain region. The central theme of this proposal is to address this critical issue with a focus on two neuronal subtypes in the hypothalamic arcuate nucleus (ARC), AgRP- and POMC- neurons, which directly sense nutrient and hormonal signals of energy availability from the periphery and relay this information to other neurons in the centra nervous system (CNS). The key function of AgRP-neurons is to respond to energy scarcity conditions, accomplished by increased expression of the orexigenic agouti-related peptide (AgRP) and neuropeptide Y (NPY) that stimulate feeding behavior and reduce energy expenditure. In contrast, POMC-neurons respond to conditions of energy abundance by suppressing feeding and increasing energy expenditure primarily via the upregulation of α-melanocyte-stimulating hormone (αMSH), a proteolytic product of pro-opiomelanocortin (POMC) (1). Islet-1 (Isl1), a member of the LIM-homeodomain (LIM-HD) transcription factor family, plays crucial roles in determining cell fates during the development of several organs, such as spinal motor neurons and endocrine pancreatic islet cells (x). Expression of Isl1 has been reported in several regions of the hypothalamus (xx, xx). We also discovered that Isl1 is highly expressed in the ARC of both embryonic and postnatal mouse brains. Our analyses of conditional Isl1-null mice revealed that deletion of Isl1 in the hypothalamus results in postnatal death, associated with drastically reduced body size and abrogation in the expression of AgRP, NPY and POMC by ARC neurons. We also found critical roles of Isl1 in postnatal metabolic function of AgRP-neurons. Based on these seminal findings, we will test the hypothesis that Isl1 acts as a critical dual regulator of 1) the specification/development and 2) the postnatal function of AgRP- and POMC-neurons by coordinating a cohort of genes that establish the identity, maturation and energy homeostasis action of these neurons in developing and postnatal hypothalamus. We will test this hypothesis in the following three specific aims using an ensemble of cellular, biochemical, genetic, and unbiased genome-wide approaches. In the first aim, we wish to determine the temporal and spatial pattern of Isl1 expression in the developing and postnatal mouse hypothalamus. In the second aim, we will define the roles of Isl1 in the development and the energy balance function of AgRP- and POMC-neurons. In the final aim, we will define the target genes of Isl1 and its partner transcription factors that direct the developmental specification, maturation and function of the arcuate AgRP- and POMC-neurons.

描述（由申请人提供）：下丘脑在体内平衡和能量代谢中发挥着关键作用，因此下丘脑发育缺陷会导致严重的病理状况，包括糖尿病和肥胖症 (1) 然而，下丘脑细胞类型的多样性是如何确定的。并且仍然不明确，部分原因是这一重要大脑区域的解剖复杂性。该提案的中心主题是解决这一关键问题，重点关注下丘脑的两种神经元亚型。弓状核 (ARC)、AgRP 和 POMC 神经元，直接感知来自外周的营养和能量可用性的激素信号，并将此信息传递给中枢神经系统 (CNS) 中的其他神经元。 AgRP 神经元的关键功能是。通过增加促食欲刺鼠相关肽 (AgRP) 和神经肽 Y (NPY) 的表达来应对能量短缺情况，从而刺激进食行为并减少能量消耗。 POMC 神经元主要通过上调 α-黑素细胞刺激激素 (αMSH)（阿片黑皮质素原 (POMC) 的蛋白水解产物 (Isl1)）来抑制摄食和增加能量消耗，从而对能量充足的情况做出反应 (1)。）是 LIM 同源域 (LIM-HD) 转录因子家族的成员，在多个器官（例如脊髓运动神经元和内分泌胰岛细胞 (x)。我们还发现 Isl1 在胚胎和出生后小鼠大脑的 ARC 中高表达。 -null 小鼠显示，下丘脑中 Isl1 的缺失会导致出生后死亡，与体型显着减小以及 AgRP、NPY 表达的废除相关我们还发现 Isl1 在 AgRP 神经元出生后代谢功能中的关键作用，基于这些开创性的发现，我们将检验 Isl1 作为 1）规范/发育和 2 的关键双重调节器的假设。我们将测试 AgRP 和 POMC 神经元的出生后功能，通过协调一组基因来确定这些神经元在发育和出生后下丘脑中的身份、成熟和能量稳态作用。使用细胞、生化、遗传和无偏见全基因组方法的集合来实现以下三个具体目标的假设。第一个目标是，我们希望确定发育中和出生后小鼠下丘脑中 Isl1 表达的时间和空间模式。在第二个目标中，我们将定义 Isl1 在 AgRP 和 POMC 神经元的发育和能量平衡功能中的作用。在最终目标中，我们将定义 Isl1 的靶基因及其指导的伙伴转录因子。弓状 AgRP 和 POMC 神经元的发育规范、成熟和功能。