Developmental Regulation of Potassium Channels in Hypothalamic Neurons Governing Energy Homeostasis

控制能量稳态的下丘脑神经元钾通道的发育调节

• 批准号: 10701674
• 负责人: Megan A Doczi
• 金额: $ 13.31万
• 依托单位: NORWICH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-09 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701674
• 关键词: Affect; Award; Biological Assay; Birds; Body Weight; Brain; Brain region; Cell Nucleus; Cells; Central Nervous System; Complex; Data; Development; Diabetes Mellitus; Early Intervention; Eating; Electrophysiology (science); Embryo; Energy Metabolism; Equilibrium; Exposure to; Family; Food Energy; Gene Expression; Goals; Health; Homeostasis; Hormonal; Hormones; Human; Hypothalamic structure; Immunofluorescence Immunologic; Insulin; Insulin Receptor; Intervention; Ion Channel; Ion Channel Gating; Knowledge; Knowledge Discovery; Laboratories; Life; Long-Term Effects; Maintenance; Measures; Mediating; Medical; Membrane Potentials; Metabolic; Metabolic Diseases; Metabolic hormone; Metabolism; Modeling; Neurons; Nutritional; Obesity; Pathway interactions; Pattern; Peripheral; Pharmacologic Substance; Phosphotransferases; Physiological; Positioning Attribute; Potassium Channel; Predisposition; Prevention strategy; Process; Property; Proteins; Publishing; Receptor Signaling; Regulation; Research; Research Personnel; Rest; Role; Signal Transduction; Slice; System; Techniques; Testing; Time; Tissues; Training; Tyrosine Phosphorylation; Universities; Up-Regulation; Voltage-Gated Potassium Channel; Work; insight; insulin sensitivity; insulin signaling; intrauterine environment; member; neuronal excitability; novel therapeutic intervention; receptor; sensor; treatment strategy; undergraduate student; voltage

PROJECT SUMMARY/ABSTRACT The long-term goal of this work is to understand how metabolic signaling can alter the functional development of energy homeostasis pathways through the modulation of specific ion channels in hypothalamic neurons. The hypothalamus is a brain region that mediates the regulation of critical metabolic processes throughout the body. Specialized hypothalamic neurons can integrate the homeostatic balance between food intake and energy expenditure via peripheral signals, a process that may become dysregulated in obesity and other metabolic disorders. Evidence indicates that the function of Kv1.3, a voltage-gated potassium channel governing neuronal excitability and resting membrane potential, can be modulated by circulating peripheral signals such as insulin, although the role of this modulation in the early development of hypothalamic circuits remains unclear. The central hypothesis of this proposal is that insulin modulates the developmental function of Kv1.3 in hypothalamic neurons governing energy homeostasis. The central hypothesis will be tested with the following specific aims: (1) identify the developmental colocalization of Kv1.3 and the insulin receptor (IR) in specific hypothalamic nuclei governing energy homeostasis, (2) define how hypothalamic Kv1.3 channels are functionally modulated by insulin during development, and (3) determine the role of heteromultimeric Kv1 complexes in channel regulation of the developing hypothalamus. In order to achieve the experimental objectives, immunofluorescence will be used to identify Kv1.3 and IR protein at different developmental stages in specific hypothalamic nuclei involved in metabolic function. To test the hypothesis that insulin regulates neuronal activity via suppression of Kv1.3, brain slices of the avian hypothalamus will be exposed to exogenous insulin and changes in ion channel function will be recorded using electrophysiological techniques. Subsequently, in ovo hormone application will be used to determine the long-term effect of insulin exposure on the electrophysiological function of Kv1.3 in hypothalamic neurons at critical embryological time points. The physiological effects of Kv1 channel heteromultimerization on the insulin-sensitive function of Kv1.3 channels in hypothalamic neurons will also be explored. This proposal will be the first to elucidate the developmental role of insulin exposure on Kv1.3 channel function in hypothalamic neurons governing energy homeostasis. Examining the developmental regulation of Kv1.3 in this embryonic system will provide new insight fundamental to understanding the early patterning of hypothalamic circuits and may provide further evidence targeting these potassium channels in the pharmaceutical intervention of metabolic disorders such as diabetes and obesity.

项目摘要/摘要 这项工作的长期目标是了解代谢信号如何改变功能发育 通过调节下丘脑神经元中特定离子通道的能量动态平衡通路。这个 下丘脑是大脑的一个区域，在整个大脑中调节关键的代谢过程。 尸体。专门的下丘脑神经元可以整合食物摄入量和食物之间的动态平衡。 通过外周信号的能量消耗，这一过程可能会在肥胖和其他疾病中变得失调 代谢紊乱。有证据表明，电压门控性钾通道Kv1.3的功能 循环外周调节神经元兴奋性和静息膜电位 信号，如胰岛素，尽管这种调制在下丘脑电路早期发育中的作用 目前仍不清楚。这一建议的中心假设是胰岛素调节发育 Kv1.3在下丘脑神经元调节能量动态平衡中的作用。中心假设将是 测试的具体目标如下：(1)确定Kv1.3和胰岛素的发育共定位 下丘脑特定核团中控制能量平衡的受体(IR)，(2)定义下丘脑如何 Kv1.3通道在发育过程中受胰岛素的功能调节，以及(3)决定Kv1.3通道的作用 异多聚体KV1复合体在发育中的下丘脑通道调节中的作用。为了实现这一目标 实验目的：将免疫荧光法用于鉴定Kv1.3和IR蛋白的不同 参与代谢功能的特定下丘脑核团的发育阶段。来检验这一假设 胰岛素通过抑制Kv1.3调节神经元活动，鸟下丘脑脑片将 暴露于外源性胰岛素和离子通道功能的变化将使用电生理记录 技巧。随后，在卵子中应用激素来确定胰岛素的长期疗效。 胚胎发育临界期对下丘脑神经元Kv1.3电生理功能的影响 积分。Kv1通道异构化对Kv1.3胰岛素敏感功能的生理影响 下丘脑神经元中的通道也将被探索。这项提案将是第一个澄清 胰岛素暴露对下丘脑能量支配神经元Kv1.3通道功能的发育作用 动态平衡。研究Kv1.3在这个胚胎系统中的发育规律将提供新的 洞察力是理解下丘脑回路早期模式的基础，并可能进一步提供 以这些钾通道为靶点的药物干预代谢紊乱的证据 糖尿病和肥胖症。