Augmenting Pulsatile Growth Hormone: Metabolic Effects in HIV-Infection

描述（由申请人提供）：超过一半的hiv感染者现在表现出身体脂肪分布的变化，包括内脏脂肪增加和周围脂肪萎缩。随着这些变化，感染艾滋病毒的患者患胰岛素抵抗、糖尿病、血脂异常和心血管疾病的风险增加。本研究旨在研究一种通过使用生长激素释放激素（GHRH1-44）增加内源性生长激素（GH）分泌来减少腹部脂肪和降低HIV感染代谢风险的新策略。这一策略的基本原理源于数据，即腹部脂肪堆积的hiv感染患者相对缺乏生长激素，以及临床观察，在其他生长激素缺乏人群中替代生长激素可改善身体成分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，GHRH1-44在此应用中的使用是为了增加生理性垂体生长激素分泌，而不是提供脉动性外源性替代。我们的初步数据表明，GHRH1-44增加了内源性搏搏性生长激素的分泌，我们假设与外源性rhGH相比，这将导致更大的疗效和更少的副作用。先前的研究表明，GHRH1-44可以减少内脏脂肪堆积，改善血脂异常。在这个提议中，我们假设GHRH1-44也会减少肝脏和肌肉中的异位脂肪，潜在地改善胰岛素抵抗。本申请中提出了两项研究——短期比较GHRH1-44与rhGH对内源性GH搏动性和胰岛素敏感性的影响，以及一项为期1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。总之，来自这些研究的数据将表征GHRH1-44的代谢作用，此外，将通过对比GHRH1-44与rhGH的作用来探索GH搏动性的生理学重要性。有了这些目标，拟议的研究将增强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HIV代谢并发症的新治疗策略。

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.