New Approaches to the Evaluation and Treatment of Acromegaly

描述（由申请人提供）：这个项目的总体目标是支持我作为一个独立的以患者为导向的研究者和成功的导师的持续专业发展。我研究的一个重点是建立和验证基于高度敏感的生长激素和igf - 1测量的肢端肥大症治疗的最佳生化终点，利用我建立的一个独特的大型患者队列。我们现在也在评估肢端肥大症治疗的临床终点。这项最近的工作已经确定了肢端肥大症患者体内成分的新变化。这些发现使我们假设gh - igf - 1过量的脂肪组织（AT）特异性失调和脂肪营养不良的发生，其特征是中央AT库减少而肌肉中AT增加，可能导致胰岛素抵抗和心血管风险增加。肢端肥大症治疗可以逆转这种脂肪营养不良，但在一些患者中，这可能会增加中枢AT储存，从而增加AT和循环中的炎症。这个应用程序的前四个科学目标，由我的R01 DK064720资助，测试脂肪营养不良及其恢复如何影响AT炎症、脂肪因子、食欲激素、内皮功能、心血管风险标志物和肢端肥大症的长期结果。我们将利用新的技术来研究肢端肥大症，包括通过磁共振光谱检查肌肉脂质，脂肪组织的巨噬细胞浸润和炎症以及内皮细胞的内皮功能障碍标记。了解这种脂肪营养不良的后果及其逆转是至关重要的，因为它们可能具有长期的临床意义。这项研究是唯一一项由美国国立卫生研究院资助的肢端肥大症研究，它将提供新的重要数据，这些数据也适用于我们对其他临床环境中生长激素使用和过度使用的影响的理解。这一应用包括一项关于生长激素/ igf - 1过量及其治疗对骨骼的影响的新研究（Aim 5）。肢端肥大症骨折增加，但骨密度（BMD）不降低。利用HRpQCT对骨结构的新评估以及骨密度、骨折患病率和骨代谢标志物的测量，我们将在其他终点中确定，骨密度看似正常的患者的骨结构（通过HRpQCT）是否因骨大小增加而受损。我富有成效的、正在进行的、由NIH资助的临床研究项目，我成功的指导记录，以及我16年以患者为导向的研究经验，使我非常适合K24奖的续期。K24提供的额外资金将使我能够在NIH资助的面向患者的研究和指导上保持高水平的努力。没有它，我的临床和管理职责将大大增加，对当前和未来学员的培训产生不利影响。哥伦比亚大学的制度环境，拥有强大而多样化的内分泌部门，CTSA， CRC，糖尿病和肥胖研究中心，是吸引研究员和进行研究的理想场所。这个奖项的续签是一个理想的机制，以确保继续支持我需要保持我作为导师和临床研究者的成功。

DESCRIPTION (provided by applicant): The overall goal of this project is to support my continued professional development as an independent patient-oriented investigator and successful mentor. A focus of my research has been to establish and validate optimal biochemical endpoints for acromegaly therapy based on highly sensitive GH and IGF-I measurements utilizing a uniquely large cohort of patients that I have established. We are now also assessing clinical endpoints of acromegaly therapy. This recent work has identified novel changes in body composition in patients with acromegaly. These findings have led us to hypothesize that a GH-IGF-I excess specific dysregulation of adipose tissue (AT) and lipodystrophy occur which is characterized by reduced central AT depots yet increased AT in muscle and may contribute to insulin resistance and increased cardiovascular risk. Acromegaly therapy may reverse this lipodystrophy, but in some patients this may increase central AT stores and thereby increase inflammation in AT as well as in circulation. This application's first 4 scientific aims, funded by my R01 DK064720, test how the lipodystrophy and its recovery affect AT inflammation, adipokines, appetite hormones, endothelial function, cv risk markers and long-term outcome in acromegaly. We will utilize techniques novel to acromegaly studies including examinations of muscle lipid by MR spectroscopy, adipose tissue for macrophage infiltration and inflammation and endothelial cells for markers of endothelial dysfunction. Understanding the consequences of this lipodystrophy and its reversal are crucial because they may be of long-term clinical significance. This study, the only one on acromegaly funded by the NIH, will provide novel important data which is also applicable to our understanding of the effects of GH use and over-use in other clinical settings. This application includes a new investigation (Aim 5) into the affect of GH/IGF-I excess and its treatment on the skeleton. Fractures are increased in acromegaly, but bone mineral density (BMD) is not reduced. Utilizing the novel assessment of bone architecture by HRpQCT along will BMD, fracture prevalence and bone metabolism marker measurements we will determine, among other endpoints, if bone architecture (by HRpQCT) is impaired in patients with a seemingly normal BMD due to an artifact of increased bone size. My productive, ongoing, NIH funded clinical research program, my successful mentoring track record and my 16 years of experience in patient-oriented research make me well suited for renewal of the K24 award. The additional funds provided by the K24 will allow me to maintain my high level of effort on NIH funded patient-oriented research and mentoring. Without it my clinical and administrative duties would be greatly increased with detrimental impact on current and future mentees' training. The institutional environment at Columbia, with a strong and diverse Endocrine Division, CTSA, CRC, Diabetes and Obesity Research Centers, is ideal for attracting fellows and conducting our research. Renewal of this award is an ideal mechanism to ensure the continued support I need to maintain my success as a mentor and clinical researcher. PUBLIC HEALTH RELEVANCE: Acromegaly, a rare disease due to a growth hormone producing pituitary tumor, is associated with increased morbidity and mortality. In this project we will utilize modern biochemical methods, novel techniques and a uniquely large, ongoing prospective acromegaly cohort study to characterize novel features of acromegaly including an abnormal fat distribution that may contribute significantly to its increased morbidity and mortality. Our study will lead to important knowledge about the effects GH and IGF-I on body composition, adipose tissue inflammation, endothelial dysfunction, bone density and cardiovascular risk, which is also applicable to our understanding of the effects of GH use and over-use in other clinical settings.