New Approaches to the Evaluation and Treatment of Acromegaly

描述（由申请人提供）：本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继续专业发展。我的研究重点是建立和验证肢端肥大症治疗的最佳生化终点，基于高度敏感的GH和IGF-I测量，利用我建立的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。这项最新的研究发现了肢端肥大症患者身体成分的新变化。这些发现使我们假设脂肪组织（AT）和脂肪代谢障碍发生GH-IGF-I过量特异性失调，其特征是中央AT库减少，但肌肉中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，这可能会增加中央AT储存，从而增加AT以及循环中的炎症。该应用程序的前4个科学目标，由我的R 01 DK 064720资助，测试脂肪代谢障碍及其恢复如何影响AT炎症，脂肪因子，食欲激素，内皮功能，CV风险标志物和肢端肥大症的长期结局。我们将利用肢端肥大症研究的新技术，包括通过MR波谱检查肌肉脂质、脂肪组织巨噬细胞浸润和炎症以及内皮细胞内皮功能障碍的标志物。了解这种脂肪代谢障碍及其逆转的后果是至关重要的，因为它们可能具有长期的临床意义。这项研究是NIH资助的唯一一项关于肢端肥大症的研究，将提供新的重要数据，这些数据也适用于我们对GH使用和过度使用在其他临床环境中的影响的理解。本申请包括一项新的研究（目的5）GH/IGF-I过量及其对骨骼的治疗的影响。肢端肥大症的骨折增加，但骨矿物质密度（BMD）不降低。利用通过HRpQCT沿着BMD、骨折患病率和骨代谢标志物测量的骨结构的新评估，我们将确定在其他终点中，骨结构（通过HRpQCT）是否在具有看似正常的BMD的患者中由于骨大小增加的伪影而受损。我富有成效的，持续的，NIH资助的临床研究计划，我成功的指导记录和我在以患者为导向的研究方面的16年经验使我非常适合K24奖的更新。K24提供的额外资金将使我能够在NIH资助的以患者为导向的研究和指导方面保持高水平的努力。如果没有它，我的临床和行政职责将大大增加，对当前和未来学员的培训产生不利影响。哥伦比亚的机构环境，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，是吸引研究员和开展研究的理想场所。这个奖项的更新是一个理想的机制，以确保继续支持我需要保持我作为一个导师和临床研究人员的成功。 公共卫生相关性：肢端肥大症，一种罕见的疾病，由于生长激素产生的垂体瘤，是与发病率和死亡率增加。在这个项目中，我们将利用现代生物化学方法，新技术和独特的大型，正在进行的前瞻性肢端肥大症队列研究，以表征肢端肥大症的新特征，包括异常脂肪分布，可能会显着增加其发病率和死亡率。我们的研究将获得有关GH和IGF-I对身体组成、脂肪组织炎症、内皮功能障碍、骨密度和心血管风险的影响的重要知识，这也适用于我们对GH使用和过度使用的影响的了解在其他临床环境中。

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.