Epigenetic Mechanisms and Developmental Actions of Leptin in the Hypothalamus

下丘脑瘦素的表观遗传机制和发育作用

• 批准号: 9220228
• 负责人: RICHARD B SIMERLY
• 金额: $ 60.31万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9220228
• 关键词: Adipocytes; Adult; Affect; Architecture; Body Composition; Body Weight; Brain; Coupling; DNA Methylation; DNA Methylation Regulation; DNMT3a; Data; Development; Developmental Biology; Developmental Process; Eating; Endocrine; Energy Metabolism; Environmental Risk Factor; Epigenetic Process; Event; Gene Expression; Gene Expression Regulation; Genes; Goals; Homeostasis; Hormones; Hypothalamic structure; Individual; Informatics; Leptin; Life; Maps; Measures; Mediating; Metabolic; Methylation; Microdissection; Modification; Molecular; Mus; Neurons; Nucleic Acid Regulatory Sequences; Obese Mice; Obesity; Pathway interactions; Pattern; Physical activity; Physiological; Physiology; Play; Population; Predisposition; Presynaptic Terminals; Process; Regulation; Research; Role; Sensory; Signal Transduction; Site; Specific qualifier value; System; Testing; Transgenic Mice; Wild Type Mouse; Work; base; cell type; critical developmental period; critical period; energy balance; epigenetic regulation; epigenomics; genome-wide; histone modification; loss of function; metabolic phenotype; nerve supply; neurodevelopment; neuron development; neuronal circuitry; obesity risk; paraventricular nucleus; postnatal; postsynaptic neurons; prenatal; relating to nervous system; transcriptomics

PROJECT SUMMARY Accumulating data indicate that environmental influences during prenatal and early postnatal development can affect individual susceptibility to obesity throughout life. The long-term goal of this line of research is to define molecular events that mediate environmental influences on development of neuronal circuitry involved in the regulation of mammalian energy homeostasis. The hypothalamus is a likely site for coupling early environmental signals to lifelong control of body weight, and neuronal projections from the arcuate (ARH) to the paraventricular (PVH) nucleus of the hypothalamus are essential in regulating energy balance. The adipocyte-derived hormone leptin directs formation of neuronal projections from the ARH to the PVH, and distinct aspects of body weight regulation are dependent on these developmental actions of leptin, specifically during a postnatal critical period. The mechanisms that restrict formation of neuronal pathways to discrete developmental periods are largely unknown. But DNA methylation, which appears to function as a major epigenetic mark stably modulating expression of genes that control development in a variety of neural systems, is an excellent candidate. The overall hypotheses of the proposed research are that 1) the critical developmental window during which ARH neurons are responsive to the neurotrophic actions of leptin is dictated by epigenetic mechanisms, and 2) cell type-specific methylation of genic and other regulatory regions is essential for accurate targeting of functionally distinct classes of neurons, with consequences for normal metabolic physiology. We will test these hypotheses by mapping cell type-specific epigenetic expression modules in the ARH during and after closure of this critical developmental window (Aim 1). In addition, we will identify leptin-mediated epigenetic changes within subpopulations of ARH neurons that display leptin- dependent patterns of projections to the PVH (Aim 2). We will also use transgenic mice with targeted disruption of the DNA methylation machinery to determine if DNA methylation is required for closure of the critical developmental period for the neurotrophic action of leptin on ARH projections and associated metabolic physiology (Aim 3). The proposed research will objectively and definitively assess whether epigenetic mechanisms specify critical periods of brain development when leptin and perhaps other environmental factors impact brain architecture and the regulation of energy balance throughout life.

项目总结 越来越多的数据表明，出生前和出生后早期的环境影响 发育可能会影响个体一生中对肥胖的易感性。这条线路的长期目标是 研究的重点是定义调节环境对发育的影响的分子事件 神经回路参与了哺乳动物能量平衡的调节。下丘脑是一种 可能是将早期环境信号与终生体重控制相结合的场所，以及神经元 从弓状核(ARH)到下丘脑室旁核(PVH)的投射是 对调节能量平衡至关重要。脂肪细胞衍生的激素瘦素指导 从ARH到PVH的神经元投射和体重调节的不同方面是 依赖于瘦素的这些发育活动，特别是在出生后的关键时期。这个 将神经元通路的形成限制在离散的发育期的机制主要是 未知。但DNA甲基化，这似乎是一个主要的表观遗传标记，稳定地调节 在各种神经系统中控制发育的基因的表达，是一个很好的候选者。 拟议研究的总体假设是：1)关键的发展窗口 表观遗传学决定了哪些ARH神经元对瘦素的神经营养作用有反应 机制，以及2)基因和其他调节区的细胞类型特异性甲基化对于 精确定位不同功能类别的神经元，对正常代谢产生影响 生理学。我们将通过将特定于细胞类型的表观遗传表达模块映射到 在这一关键发育窗口关闭期间和之后的ARH(目标1)。此外，我们还将 确定在ARH神经元亚群中显示瘦素的瘦素介导的表观遗传学变化 向PVH投射的依赖模式(目标2)。我们还将使用转基因小鼠进行靶向治疗 扰乱DNA甲基化机制，以确定是否需要DNA甲基化来关闭 瘦素对ARH投射的神经营养作用的关键发育期及其相关 代谢生理学(目标3)。拟议的研究将客观和明确地评估 表观遗传机制规定了大脑发育的关键时期，瘦素和其他可能的 环境因素会影响大脑的结构和一生中能量平衡的调节。