Augmenting Pulsatile Growth Hormone: Metabolic Effects in HIV-Infection

描述(由申请人提供)：现在接受艾滋病毒感染治疗的患者中，超过一半的人表现出体内脂肪分布的变化，包括内脏脂肪增加和外周脂肪萎缩。伴随着这些变化，艾滋病毒感染患者患胰岛素抵抗、糖尿病、血脂异常和心血管疾病的风险增加。这项赠款提案研究了一种新的策略，通过使用生长激素释放激素(GHRH1-44)来增加内源性生长激素(GH)的分泌，从而减少腹部脂肪和降低艾滋病毒感染的代谢风险。这一策略的理论基础来自于有数据表明，有腹部脂肪堆积的HIV感染患者相对缺乏生长激素，以及临床观察表明，在其他有生长激素缺乏的人群中进行生长激素替代可以改善身体组成并改善心脏代谢风险。与使用外源性重组人生长激素(RhGH)相比，在这一应用中使用GHRH1-44是为了增加生理性垂体GH的分泌，而不是提供通用的外源性替代。我们的初步数据显示，GHRH1-44增加了内源性脉动性生长激素的分泌，我们假设这将导致与外源性rhGH相比，更好的疗效和更少的副作用。先前的研究表明，GHRH1-44可减少内脏脂肪堆积，改善血脂紊乱。在这项建议中，我们假设GHRH1-44还将减少肝脏和肌肉中的异位脂肪，潜在地改善胰岛素抵抗。在这项应用中提出了两项研究-GHRH1-44与rhGH对内源性GH脉动性和胰岛素敏感性的短期比较，以及一项为期一年的随机安慰剂对照试验，测量GHRH1-44对脂肪分解、胰岛素敏感性和异位脂肪积累的影响。总而言之，这些研究的数据将描述GHRH1-44的代谢影响，并通过比较GHRH1-44和rhGH的影响来探索GH脉动性的生理重要性。有了这些目标，拟议的研究将增进我们对生长激素生理学的理解，并有助于开发一种潜在的重要的新的艾滋病毒代谢并发症的治疗策略。 这项申请的候选人Takara Stanley博士是一位儿科内分泌学家，在艾滋病毒感染的代谢和内分泌并发症方面具有临床研究经验。斯坦利博士的职业目标是在学术环境中进行以患者为中心的研究，重点研究身体脂肪分布的代谢和内分泌方面。在目前的提案中，斯坦利博士将通过HIV-脂肪营养不良的模型来探索这些主题。随着事业的发展，她计划将自己的研究领域扩大到腹型肥胖的儿科疾病。拟议的研究将为斯坦利博士提供多种生理学研究方法的经验和培训，包括分析激素分泌动力学、葡萄糖动态平衡和脂肪代谢的技术。此外，拟议的职业发展计划将为斯坦利博士提供统计和药物开发方面的进一步培训。该提案的导师史蒂文·格林斯普龙博士是国际公认的艾滋病毒相关内分泌和代谢并发症领域的专家。除了是一名久负盛名、资金雄厚的临床研究人员外，他还是一位成就卓著的导师，拥有指导斯坦利博士并帮助她过渡到独立所需的技能和基础设施。在格林斯普龙博士的指导下，这份申请书中提出的职业发展计划将为斯坦利博士提供成为一名独立临床研究员的培训和技能。 公共卫生相关性：该项目将确定一种名为生长激素释放激素(GHRH1-44)的新疗法的代谢影响，该疗法用于减少艾滋病毒感染和腹部增大患者的腹部脂肪和改善新陈代谢。这项研究将有助于我们了解这一治疗艾滋病毒感染并发症的重要潜在疗法，并将增加我们对生长激素如何影响糖和脂肪代谢的理解。

DESCRIPTION (provided by applicant): More than half of individuals treated for HIV-infection now demonstrate changes in body fat distribution, including increased visceral adiposity and peripheral fat atrophy. Along with these changes, HIV-infected patients are at increased risk for insulin resistance, diabetes, dyslipidemia, and cardiovascular disease. This grant proposal investigates a novel strategy to decrease abdominal fat and reduce metabolic risk in HIV- infection by augmenting endogenous growth hormone (GH) secretion through the use of growth hormone releasing hormone (GHRH1-44). The rationale for this strategy stems from data that HIV-infected patients with abdominal fat accumulation are relatively GH deficient, and from clinical observations that GH replacement in other populations with GH deficiency improves body composition and ameliorates cardiometabolic risk. The use of GHRH1-44 in this application, in contrast to the use of exogenous recombinant human GH (rhGH), is proposed in order to augment physiologic pituitary GH secretion rather than providing apulsatile exogenous replacement. Our preliminary data demonstrate that GHRH1-44 increases endogenous pulsatile growth hormone secretion, which we hypothesize will lead to greater efficacy and reduced side effects as compared to exogenous rhGH. Previous studies have demonstrated that GHRH1-44 reduces visceral fat accumulation and improves dyslipidemia. In this proposal we hypothesize that GHRH1-44 will also decrease ectopic fat in liver and muscle, potentially ameliorating insulin resistance. Two studies are proposed in this application - a short-term comparison of the effects of GHRH1-44 vs. rhGH on endogenous GH pulsatility and insulin sensitivity, and a 1 year randomized placebo-controlled trial measuring the effects of GHRH1-44 on lipolysis, insulin sensitivity, and ectopic fat accumulation. Together, data from these studies will characterize the metabolic effects GHRH1- 44 and, additionally, will explore the physiologic importance of GH pulsatility by contrasting the effects of GHRH1-44 vs. rhGH. With these goals, the proposed research will both enhance our understanding of GH physiology and contribute to the development of a potentially important new treatment strategy for metabolic complications of HIV. The candidate in this application, Dr. Takara Stanley, is a pediatric endocrinologist with clinical research experience in metabolic and endocrine complications of HIV-infection. Dr. Stanley's career goal is to perform patient-oriented research in an academic setting, focusing on the metabolic and endocrine aspects of body fat distribution. In the current proposal, Dr. Stanley will explore these themes through the model of HIV-lipodystrophy. As she progresses in her career, she plans to expand her field of investigation to pediatric conditions of abdominal obesity. The proposed studies will provide Dr. Stanley with experience and training in numerous methods of physiologic investigation, including techniques for analyzing hormone secretory dynamics, glucose homeostasis, and lipid metabolism. In addition, the proposed career development plan will provide Dr. Stanley will further training in statistics and drug development. The mentor in this proposal, Dr. Steven Grinspoon, is an internationally recognized expert in the field of HIV-associated endocrine and metabolic complications. In addition to being a well-established and well-funded clinical researcher, he is an accomplished mentor with the skills and infrastructure necessary to mentor Dr. Stanley and help her transition to independence. Along with the mentorship of Dr. Grinspoon, the career development plan proposed in this application will provide Dr. Stanley with the training and skills to become an independent clinical investigator. PUBLIC HEALTH RELEVANCE: This project will determine the metabolic effects of a new therapy, growth hormone releasing hormone (GHRH1-44), to reduce abdominal fat and improve metabolism in patients with HIV-infection and increased belly size. The research will contribute to our knowledge of this important potential therapy for complications of HIV-infection, and will also increase our understanding of how growth hormone affects sugar and fat metabolism.