Secreted Micropeptides in the Regulation of Metabolic Homeostasis

分泌微肽在代谢稳态调节中的作用

• 批准号: 9902442
• 负责人: Angie Lynn Bookout
• 金额: $ 12.25万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-28 至 2020-04-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902442
• 关键词: Adipose tissue; Advisory Committees; Affect; Amino Acids; Animals; Award; Bioinformatics; Biological Assay; Brain; Cell Nucleus; Collection; Communication; Data; Dependovirus; Diabetes Mellitus; Diet; Disease; Endocrine; Energy Metabolism; Ensure; Enterobacteria phage P1 Cre recombinase; Faculty; Fatty Liver; Foundations; Funding; Gene Expression; Generations; Genetic; Goals; Health; Heart failure; Histologic; Homeostasis; Hormones; Hypoglycemia; Hypothalamic structure; Individual; International; Knockout Mice; Lipids; Liver; Liver diseases; Maps; Measurement; Measures; Mediating; Mentored Research Scientist Development Award; Mentors; Metabolic; Metabolic Control; Metabolic dysfunction; Metabolic stress; Metabolic syndrome; Metabolism; Mission; Molecular; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Neurons; Neuropeptides; Neurosecretory Systems; Nutritional; Nutritional status; Obesity; Outcome; Pathway interactions; Peripheral; Phenotype; Plasma; Proteins; Regulation; Research; Role; Series; Signaling Molecule; Site; Stroke; Techniques; Testing; Therapeutic; Time; Tissues; Training; Work; cardiometabolism; cardiovascular health; coronary vascular disease; design; energy balance; experimental study; improved; in vivo; indexing; interest; knockout animal; metabolic phenotype; mouse model; novel; overexpression; respiratory; response; tenure track; tool

Project Summary/Abstract Cardiometabolic disease as result of metabolic syndrome continues to be a major health burden worldwide, regardless of the numerous available therapeutic strategies. Obesity and diabetes impact cardiovascular health leading to heart failure, stroke, coronary vascular disease and other indices like fatty liver disease due to perturbed metabolic homeostasis. Derangements in systemic energy homeostasis are the result of metabolic dysfunction within individual tissues as well as in defective communication between tissues. Understanding metabolic coordination within a particular tissue and throughout the body will lead to new and improved therapeutic avenues. We recently uncovered a novel class of secreted micropeptides expressed in the brain, among which is a protein we call B03. Mice with genetic deletion of B03 have elevated plasma lipids and reduced respiratory exchange rates, leading to our hypothesis that B03 has a role in metabolic homeostasis by communicating nutritional status between neurons. This proposal will determine if the micropeptide B03 is required to maintain whole body energy balance through actions within the brain. First we will characterize the metabolic outcomes of genetic deletion of B03 in the whole animal. We will subject B03 knockout animals to metabolic stress paradigms including diet induced obesity as well as severe hypoglycemia. These animals will then undergo a series of assessments using state-of-the-art techniques including metabolic cages to measure energy expenditure, neuroendocrine assays, and gene expression measurements in liver and adipose. We will next determine the exact cellular identity of neurons expressing B03 using histochemical techniques. Finally, we will delete or overexpresss B03 only in neurons using either cre-recombinase or adeno-associated virus (AAV) tools and assess the animals as stated above to determine the requirement of the brain in mediating the effects of B03 on metabolic homeostasis. Taken together, these studies will test the hypothesis that B03 is a novel neuropeptide that contributes to metabolic homeostasis by acting within the brain in response to nutritional challenge.

项目总结/摘要 由代谢综合征引起的心脏代谢疾病仍然是世界范围内的主要健康负担， 不管有多少种可用的治疗策略。肥胖和糖尿病影响心血管健康 导致心力衰竭，中风，冠状血管疾病和其他指数，如脂肪肝疾病， 代谢平衡紊乱全身能量平衡紊乱是代谢紊乱的结果。 个体组织内的功能障碍以及组织之间的通信缺陷。理解 特定组织内和整个身体的代谢协调将导致新的和改善的 治疗途径 我们最近发现了一类在大脑中表达的新型分泌性微肽，其中有一种蛋白质 我们叫B 03 B 03基因缺失的小鼠具有升高的血浆脂质和降低的呼吸交换 率，导致我们的假设，即B 03在代谢稳态的作用，通过沟通营养状况 神经元之间。该建议将确定是否需要微肽B 03来维持全身能量 通过大脑内部的活动来实现平衡。首先，我们将描述基因缺失的代谢结果， B 03在整个动物。我们将使B 03敲除动物经受代谢应激范例，包括饮食 诱发肥胖以及严重低血糖。然后，这些动物将接受一系列评估， 最先进的技术包括测量能量消耗的代谢笼，神经内分泌测定， 以及肝脏和脂肪中的基因表达测量。接下来我们将确定 用组织化学技术检测表达B 03的神经元。最后，我们将只在 使用cre-重组酶或腺相关病毒（AAV）工具， 以确定大脑在介导B 03对代谢稳态的影响中的需求。采取 总之，这些研究将验证B 03是一种新的神经肽的假设，有助于代谢 通过在大脑内对营养挑战做出反应来维持体内平衡。