Proopiomelanocortin gene expression and obesity

阿黑皮质素原基因表达与肥胖

基本信息

批准号：
10380168
负责人：
MALCOLM James LOW
金额：
$ 44.58万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10380168
关键词：
ATAC-seq Adopted Adult Affinity Affinity Chromatography Anatomy Animal Model Atlases Base Sequence Behavioral Binding Binding Sites Bioinformatics Brain CRISPR/Cas technology Cardiovascular Diseases Cell Nucleus Cells Chromatin Loop Chromatin Modeling Code Complex Conserved Sequence Data Set Development Diabetes Mellitus Distal Enhancers Equilibrium Fatty acid glycerol esters Funding Gene Expression Genes Genetic Genetic Transcription Health Homeobox Homeostasis Hormonal Hormones Human Hyperphagia Hypothalamic structure In Vitro Individual Knowledge Lactation Leptin Life Maintenance Mediating Messenger RNA Metabolic Metabolic syndrome Molecular Molecular Genetics Mus Mutant Strains Mice Neurons Nucleotides Obesity PPAR gamma Pattern Peptides Peripheral Physiological Pregnancy Pro-Opiomelanocortin Process Public Health Receptor Signaling Regulation Regulatory Pathway Ribosomes Role STAT3 gene Signal Pathway Signal Transduction Site Structure of nucleus infundibularis hypothalami Technology Testing Therapeutic Tissues Transgenic Mice Transgenic Organisms Translating conditional mutant dietary differential expression energy balance experimental study feeding hormone regulation in vivo leptin receptor mutant neural circuit novel programs psychologic rapid weight gain relating to nervous system response spatiotemporal stem cells transcription factor transcriptome sequencing

项目摘要

Project Summary Obesity predisposes humans to diabetes and cardiovascular disease and is a universal threat to health. Fat storage is dynamically controlled by orchestrated hormonal, neural and metabolic signals between the brain and periphery. Proopiomelanocortin (POMC) neurons that synthesize melanocortin peptides are a primary integrative site for these diverse signals related to energy homeostasis. In the past funding cycles, we made significant progress towards explaining how Pomc transcription is restricted to a subset of hypothalamic neurons in the arcuate nucleus. A modular locus comprised of two evolutionarily distinct enhancers, nPE1 and nPE2, directs neuron-specific Pomc expression. Targeted deletion of the individual or combination of enhancers revealed that they act synergistically during hypothalamic development and additively in adult life to maintain sufficiently robust Pomc transcription to avoid obesity. A bioinformatic analysis of core nucleotide sequence motifs within the enhancers combined with anatomic and functional interrogation of candidate homeobox transcription factors (TFs) in animal models identified a major contribution of Isl1 and Nkx2.1 in directing the unique temporal and spatial patterns of Pomc expression in the arcuate nucleus. The Rax TF also contributes to the identity of POMC neurons developmentally, but acts indirectly upstream of Isl1. Although necessary, these factors alone are not sufficient to fully account for the complexities of neuronal Pomc regulation. Translating Ribosome Affinity Purification (TRAP) seq of POMC neurons has identified additional, highly differentially expressed TF genes that are putatively involved in the control of Pomc expression. Therefore, we propose the following specific aims for this project renewal: 1) Uncover the complete genetic program controlling hypothalamic Pomc expression through the functional characterization of candidate TFs that define the early identity of POMC neurons and their maintenance throughout the entire lifetime, using mouse molecular genetics and human pluripotential stem cells (hPSCs) that can be differentiated into POMC neurons in vitro; 2) Determine the cis-acting code that defines hypothalamic Pomc expression through the in vivo functional analysis of the entire set of neuron-specific enhancers, their critical binding motifs and local insulators to assemble a fully functional transcriptional locus; and 3) Dissect the physiological significance of individual enhancers and critical motifs involved in the hormonal regulation of Pomc expression by leptin and in response to altered dietary conditions and caloric demands. These studies will provide fundamental knowledge about a gene essential for regulating body mass and possibly identify novel genetic or signaling pathways that can be exploited for therapeutic purposes.

项目摘要肥胖使人容易患糖尿病和心血管疾病，并且对健康是普遍的威胁。胖的存储由大脑和大脑之间的荷尔蒙，神经和代谢信号动态控制周边。合成黑色素质肽肽是主要综合性的蛋白酶素（POMC）神经元这些与能量稳态相关的各种信号的站点。过去的资金周期，我们做出了重要的朝着解释如何将POMC转录仅限于下丘脑神经元的子集的进展弧形核。一个模块化基因座，由两个进化不同的增强子NPE1和NPE2指导神经元特异性POMC表达。针对个人的有针对性删除或增强剂的组合表明它们在下丘脑发展和成年生活中具有协同作用，以保持足够强大 POMC转录以避免肥胖。核心核苷酸序列基序的生物信息学分析增强剂结合了候选同型转录因子的解剖学和功能性询问（TF）在动物模型中确定了ISL1和NKX2.1在指导独特的时间和弧形核中POMC表达的空间模式。 RAX TF也有助于POMC的身份神经元在发展上，但在ISL1的上游间接起作用。尽管有必要，但仅这些因素不是足以充分说明神经元POMC调节的复杂性。翻译核糖体亲和力 POMC神经元的纯化（陷阱）SEQ已确定了其他高度差异表达的TF基因推测参与了POMC表达的控制。因此，我们提出以下具体目标该项目更新：1）发现控制下丘脑POMC表达的完整遗传程序通过定义POMC神经元的早期身份的候选TF的功能表征及其使用小鼠分子遗传学和人类多能干细胞维护在整个生命周期中（HPSC）可以在体外分化为POMC神经元； 2）确定定义的顺式作用代码下丘脑POMC的表达通过整个神经元特异性集的体内功能分析增强子，其关键的结合基序和局部绝缘子，以组装功能齐全的转录基因座； 3）剖析荷尔蒙涉及的单个增强子和关键基序的生理意义通过瘦素调节POMC表达，并响应改变饮食条件和热量需求。这些研究将提供有关调节体重至关重要的基因的基本知识确定可用于治疗目的的新型遗传或信号通路。

项目成果

期刊论文数量（27）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Unraveling the central proopiomelanocortin neural circuits.

DOI：
10.3389/fnins.2013.00019
发表时间：
2013
期刊：
Frontiers in neuroscience
影响因子：
4.3
作者：
Mercer AJ;Hentges ST;Meshul CK;Low MJ
通讯作者：
Low MJ

Exaptation of transposable elements into novel cis-regulatory elements: is the evidence always strong?

DOI：
10.1093/molbev/mst045
发表时间：
2013-06
期刊：
Molecular biology and evolution
影响因子：
10.7
作者：
de Souza FS;Franchini LF;Rubinstein M
通讯作者：
Rubinstein M

V1b Receptor Antagonist SSR149415 and Naltrexone Synergistically Decrease Excessive Alcohol Drinking in Male and Female Mice.

DOI：
10.1111/acer.13544
发表时间：
2018-01
期刊：
Alcoholism, clinical and experimental research
影响因子：
0
作者：
Zhou Y;Rubinstein M;Low MJ;Kreek MJ
通讯作者：
Kreek MJ

Neuroendocrinology: New hormone treatment for obesity caused by POMC-deficiency.

神经内分泌学：针对 POMC 缺乏引起的肥胖的新激素治疗。

DOI：
10.1038/nrendo.2016.156
发表时间：
2016
期刊：
Nature reviews. Endocrinology
影响因子：
0
作者：
Low,MalcolmJ
通讯作者：
Low,MalcolmJ

17α-estradiol acts through hypothalamic pro-opiomelanocortin expressing neurons to reduce feeding behavior.

DOI：
10.1111/acel.12703
发表时间：
2018-03
期刊：
Aging cell
影响因子：
7.8
作者：
Steyn FJ;Ngo ST;Chen VP;Bailey-Downs LC;Xie TY;Ghadami M;Brimijoin S;Freeman WM;Rubinstein M;Low MJ;Stout MB
通讯作者：
Stout MB