GH Receptor Proteolysis and Shedding

GH 受体蛋白水解和脱落

基本信息

批准号：
8597925
负责人：
Stuart J Frank
金额：
--
依托单位：
BIRMINGHAM VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-10-01 至 2016-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8597925
关键词：
Acute Acute Disease Address Adenoviruses Affect Agonist Animals Binding Biochemical Biological Models Bioluminescence Caring Cell surface Cessation of life Chronic Disease Circadian Rhythms Cleaved cell Coupling Critical Illness Data Defect Diet Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Extracellular Domain Fatty acid glycerol esters Funding Gene Deletion Gene Delivery Gene Expression Glean Growth Growth Hormone Receptor Health Heart Hepatic Homeostasis Hormones Human Individual Infection Influentials Insulin-Like Growth Factor I Integral Membrane Protein Intensive Care Units Knockout Mice Knowledge Laboratories Light Lipopolysaccharides Liver Measures Mediating Messenger RNA Metabolic Metabolism Metalloproteases Modeling Mus Muscle Nutritional Nutritional status Obesity Organ Outcome Patients Physicians Physiological Pituitary Gland Proteins Proteolysis Reagent Regimen Regulation Reporting Resistance Risk Sepsis Signal Pathway Signal Transduction Somatotropin Surface System Techniques Testing Therapeutic Time Tissue Inhibitor of Metalloproteinase-3 Translating Tumor Necrosis Factor-alpha Vertebrates Veterans base circadian pacemaker clinically relevant feeding hormone sensitivity in vivo mouse model muscle form novel nutrition overexpression peptide hormone prevent receptor research study response

项目摘要

DESCRIPTION (provided by applicant): Growth hormone (GH) is a pituitary-derived peptide hormone with potent somatogenic and metabolic actions. GH binds its receptor (GHR), a cell surface transmembrane protein enriched in liver, muscle, fat, and heart to exert profound effects on fuel metabolism, muscle mass, and energy homeostasis in humans and other vertebrates. GH sensitivity is altered in the setting of acute and chronic disease states and it is uncertain whether enhancing or inhibiting GH action would be salutary in such situations; this is important, as both agonists and antagonists now exist. My laboratory has focused on understanding physiologic and pathophysiologic determinants of GH sensitivity, which is the integrated effect of GH levels, the abundance of cell surface GHR, and the coupling of GHR activation with intracellular signaling pathways. In previous and the current VA funding cycles, we uncovered a novel mechanism modulating GH responsiveness, involving a proteolytic system composed of the metalloprotease TACE (tumor necrosis factor-a cleaving enzyme) and the TACE inhibitor TIMP3 (tissue inhibitor of metalloproteinases-3) that inducibly alters surface GHR availability by proteolytically shedding the receptor extracellular domain. However, the extent to which this metalloproteolytic system modulates GH signaling in physiological and pathophysiological states is unknown. Realizing that GH levels vary diurnally and with nutritional status, we recently examined whether such factors affect GHR abundance and GH sensitivity. Our preliminary data in mice suggest that hepatic GHR availability and corresponding GH sensitivity vary in a time-of-day-dependent fashion coordinate with the level of TIMP3. Furthermore, diet-induced obesity also affects hepatic GHR abundance. In light of recent reports, we believe understanding how these physiologic and pathophysiologic variables affect GH sensitivity will be crucial to rationally exploit GH-enhancing or -antagonistic therapeutic strategies in critically-ill individuals. In this proposal, we will test two main hypotheses: 1) Hepatic GHR abundance is metalloproteolytically modulated in a time-of-day-dependent fashion. Nutritional factors also affect hepatic GHR abundance, but at a transcriptional level. Both forms of regulation contribute to GH sensitivity and energy homeostasis in the steady state. 2) Critical illness, exemplified by sepsis, acutely desensitizes the liver to GH via TACE- mediated GHR proteolysis. Net effects of time-of-day- and diet-determined GHR abundance and timing and degree of critical illness determine acute hepatic GH responsiveness and may thus impact the course of illness. We will use novel mouse model systems and reagents and techniques we have developed to pursue two specific objectives: 1. Examine in mice potential mechanisms of diurnal variation in liver GHR levels and the impact of such time-of-day effects on hepatic GH sensitivity. 2. Determine how the time of day and feeding regimen impact the propensity of acute illness to modulate hepatic GH sensitivity, using a mouse model of sepsis (lipopolysaccharide (LPS) administration). Successful completion of these studies will definitively ascribe the response of hepatic GH sensitivity to clinically relevant acute illness, enabling rational therapeutic exploitation of the GH axis in sepsis and other forms of critical illness.

描述（由申请人提供）：生长激素（GH）是一种垂体衍生的肽激素，具有有效的生长和代谢作用。 GH 与其受体 (GHR) 结合，这是一种富含于肝脏、肌肉、脂肪和心脏的细胞表面跨膜蛋白，对人类和其他脊椎动物的燃料代谢、肌肉质量和能量稳态产生深远影响。 GH 敏感性在急性和慢性疾病状态下会发生改变，并且不确定在这种情况下增强或抑制 GH 作用是否有益；这很重要，因为现在存在激动剂和拮抗剂。我的实验室致力于了解 GH 敏感性的生理和病理生理决定因素，即 GH 水平、细胞表面 GHR 丰度以及 GHR 激活与细胞内信号通路耦合的综合效应。在之前和当前的 VA 资助周期中，我们发现了一种调节 GH 反应性的新机制，涉及由金属蛋白酶 TACE（肿瘤坏死因子 - 裂解酶）和 TACE 抑制剂 TIMP3（金属蛋白酶组织抑制剂 - 3）组成的蛋白水解系统，通过蛋白水解脱落受体胞外域来诱导改变表面 GHR 可用性。然而，这种金属蛋白水解系统在生理和病理生理状态下调节 GH 信号传导的程度尚不清楚。认识到 GH 水平每日变化并随营养状况变化，我们最近研究了这些因素是否影响 GHR 丰度和 GH 敏感性。我们在小鼠中的初步数据表明，肝脏 GHR 可用性和相应的 GH 敏感性随 TIMP3 水平以一天中时间依赖性方式变化。此外，饮食引起的肥胖也会影响肝脏 GHR 丰度。根据最近的报告，我们相信了解这些生理和病理生理变量如何影响 GH 敏感性对于在危重个体中合理利用 GH 增强或拮抗治疗策略至关重要。在这个根据建议，我们将测试两个主要假设：1）肝脏 GHR 丰度以一天中时间依赖性方式通过金属蛋白水解进行调节。营养因素也会影响肝脏 GHR 丰度，但影响的是转录水平。两种形式的调节都有助于稳定状态下的 GH 敏感性和能量稳态。 2) 危重疾病，例如脓毒症，通过 TACE 介导的 GHR 蛋白水解使肝脏对 GH 急剧脱敏。一天中的时间和饮食决定的 GHR 丰度以及危重疾病的时间和程度的净效应决定了急性肝脏 GH 反应性，因此可能影响病程。我们将使用我们开发的新型小鼠模型系统以及试剂和技术来实现两个具体目标： 1. 在小鼠中检查肝脏 GHR 水平昼夜变化的潜在机制以及这种一天中的时间效应对肝脏 GH 敏感性的影响。 2. 使用脓毒症小鼠模型（脂多糖 (LPS) 给药）确定一天中的时间和喂养方案如何影响急性疾病调节肝脏 GH 敏感性的倾向。这些研究的成功完成将明确地将肝脏 GH 敏感性的反应归因于临床相关的急性疾病，从而能够合理地利用 GH 轴治疗脓毒症和其他形式的危重疾病。