New Approaches to the Evaluation and Treatment of Acromegaly

描述(由申请者提供)：这个项目的总体目标是支持我作为一名独立的、以患者为中心的调查员和成功的导师的持续专业发展。我的研究重点之一是利用我建立的独特的大量患者队列，基于高度敏感的GH和IGF-I测量，建立和验证肢端肥大症治疗的最佳生化终点。我们现在也在评估肢端肥大症治疗的临床终点。这项最近的工作发现肢端肥大症患者的身体成分发生了新的变化。这些发现使我们推测GH-IGF-I过度的脂肪组织特异性调节失调(AT)和脂营养不良的发生，其特征是中央AT储存库减少，但肌肉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的储存，从而增加AT和循环中的炎症。这个应用程序的前4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肢端肥大症的AT炎症、脂肪因子、食欲激素、内皮功能、血管风险标记物和长期结果。我们将利用新技术进行肢端肥大症的研究，包括用磁共振波谱检查肌肉脂肪，用脂肪组织检查巨噬细胞和炎症，用内皮细胞检查内皮功能障碍的标志。了解这种脂肪营养不良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。这项研究是由美国国立卫生研究院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，也适用于我们理解生长激素在其他临床环境中的使用和过度使用的影响。这一应用包括一项新的研究(目标5)，即GH/IGF-I过量及其对骨骼的治疗。肢端肥大症患者骨折增多，但骨密度(BMD)并未降低。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测量，我们将确定(通过HRpQCT)骨结构异常的患者是否由于骨大小增加的伪影而受损。我富有成效的、持续的、由NIH资助的临床研究计划、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续签K24奖。K24提供的额外资金将使我能够保持在NIH资助的以患者为导向的研究和指导方面的高水平努力。如果没有它，我的临床和行政职责将大大增加，并对当前和未来受训者的培训产生不利影响。哥伦比亚大学拥有强大而多样的内分泌科、CTSA、CRC、糖尿病和肥胖研究中心，其制度环境非常适合吸引研究员和开展我们的研究。续签这一奖项是一个理想的机制，可以确保我作为一名导师和临床研究人员的成功所需的持续支持。 公共卫生相关性：肢端肥大症是一种罕见的疾病，由一种产生生长激素的垂体瘤引起，与发病率和死亡率的增加有关。在这个项目中，我们将利用现代生化方法、新技术和一项独特的、正在进行的大型前瞻性肢端肥大症队列研究来描述肢端肥大症的新特征，包括可能导致其发病率和死亡率增加的异常脂肪分布。我们的研究将有助于了解GH和IGF-I对体成分、脂肪组织炎症、内皮功能障碍、骨密度和心血管风险的影响，这也适用于我们理解GH在其他临床环境中的使用和过度使用的影响。

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.