GH Receptor Proteolysis and Shedding

GH 受体蛋白水解和脱落

• 批准号: 8963445
• 负责人: Stuart J Frank
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 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/8963445
• 关键词: Acute; Acute Disease; Address; 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; Patient risk; Patients; Physicians; Physiological; Pituitary Gland; Proteins; Proteolysis; Reagent; Regimen; Regulation; Reporting; Resistance; Risk; Sepsis; Signal Pathway; Signal Transduction; Somatotropin; Surface; System; TIMP3 gene; TNF gene; Techniques; Testing; Therapeutic; Time; Translating; Vertebrates; Veterans; adenoviral-mediated; base; circadian pacemaker; clinically relevant; feeding; hormone sensitivity; in vivo; mouse model; muscle form; novel; nutrition; overexpression; peptide hormone; prevent; receptor; research study; response; Acute; Acute Disease; Address; 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; Patient risk; Patients; Physicians; Physiological; Pituitary Gland; Proteins; Proteolysis; Reagent; Regimen; Regulation; Reporting; Resistance; Risk; Sepsis; Signal Pathway; Signal Transduction; Somatotropin; Surface; System; TIMP3 gene; TNF gene; Techniques; Testing; Therapeutic; Time; Translating; Vertebrates; Veterans; adenoviral-mediated; base; circadian pacemaker; clinically relevant; feeding; hormone sensitivity; in vivo; mouse model; muscle form; novel; nutrition; overexpression; peptide hormone; prevent; receptor; research study; response

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，具有有效的种植和代谢作用。 GH结合其受体（GHR），一种细胞表面的跨膜蛋白富含肝脏，肌肉，脂肪和心脏，对人类和其他脊椎动物中的燃料代谢，肌肉质量和能量稳态产生深远的影响。在急性和慢性疾病状态的情况下，GH敏感性会改变，在这种情况下，不确定增强或抑制GH作用是有益的。这很重要，因为激动剂和对手现在都存在。我的实验室专注于理解GH灵敏度的生理和病理生理决定因素，这是GH水平的综合作用，丰富的细胞表面GHR以及GHR激活与细胞内信号通路的偶联。在以前和当前的VA资金循环中，我们发现了一种新的机制，该机制调节了GH的反应性，涉及由金属蛋白酶TACE组成的蛋白水解系统（肿瘤坏死因子 - 裂解酶）和TACE抑制剂Timp3（tace抑制剂timp3）（通过浓度抑制金属蛋白酶-3）表面表面构成的蛋白质抑制剂，使金属蛋白酶抑制剂构成蛋白酶 - 金属蛋白酶 - 3） 领域。但是，这种金属蛋白溶解系统在生理和病理生理状态中调节GH信号的程度尚不清楚。意识到GH水平在昼夜差异和营养状态变化，我们最近研究了此类因素是否影响GHR的丰度和GH敏感性。我们在小鼠中的初步数据表明，肝GHR的可用性和相应的GH敏感性在与Timp3级别的日期依赖性时尚坐标中有所不同。此外，饮食引起的肥胖症也会影响肝GHR的丰度。鉴于最近的报告，我们相信了解这些生理和病理生理变量如何影响GH敏感性对于在批判性人群中合理利用GH的增强或 - 抗抗治疗策略至关重要。在这个 提案，我们将检验两个主要的假设：1）肝GHR丰度以依赖日的方式进行金属蛋白溶液调节。营养因素还会影响肝GHR的丰度，但在转录水平上。两种形式的调节都在稳态下有助于GH灵敏度和能量稳态。 2）通过败血症举例说明的危害疾病，通过TACE介导的GHR蛋白水解使肝脏急剧脱敏。日常时间和饮食时间的GHR丰度以及危重疾病程度的净影响决定了急性肝GH的反应能力，因此可能会影响疾病的进程。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追求两个特定的目标：1。在小鼠中检查肝脏GHR水平的昼夜变化的潜在机制，以及这种日期影响对肝GH敏感性的影响。 2.使用败血症的小鼠模型（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倾向调节肝GH敏感性。这些研究的成功完成将确定地归因于肝GH敏感性对临床相关急性疾病的敏感性，从而使GH轴的理性治疗剥削能够以败血症和其他形式的危重疾病。