New Approaches to the Evaluation and Treatment of Acromegaly

描述（由申请人提供）：该项目的总体目标是支持我作为一名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。我的研究重点是利用我建立的独特的大型患者队列，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了肢端肥大症患者身体成分的新变化。这些发现使我们推测，脂肪组织 (AT) 的 GH-IGF-I 过度特异性失调和脂肪营养不良会发生，其特征是中枢 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。肢端肥大症治疗可能会逆转这种脂肪营养不良，但在某些患者中，这可能会增加中枢 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 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、CV 风险标记和肢端肥大症的长期结果。我们将利用肢端肥大症研究的新颖技术，包括通过磁共振波谱检查肌肉脂质、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志物检查。了解这种脂肪营养不良的后果及其逆转至关重要，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，将提供新颖的重要数据，这些数据也适用于我们了解 GH 使用和过度使用在其他临床环境中的影响。该应用包括一项关于 GH/IGF-I 过量影响及其对骨骼治疗的新研究（目标 5）。肢端肥大症患者骨折会增加，但骨矿物质密度 (BMD) 不会降低。利用 HRpQCT 对骨结构的新颖评估以及 BMD、骨折发生率和骨代谢标志物测量，除其他终点外，我们将确定 BMD 看似正常的患者的骨结构（通过 HRpQCT）是否因骨尺寸增加的伪影而受损。我富有成效、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在以患者为导向的研究方面 16 年的经验，使我非常适合续签 K24 奖项。 K24 提供的额外资金将使我能够继续致力于 NIH 资助的以患者为导向的研究和指导。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。哥伦比亚大学的机构环境拥有强大且多元化的内分泌部门、CTSA、CRC、糖尿病和肥胖研究中心，非常适合吸引研究员和开展我们的研究。续签该奖项是一种理想的机制，可以确保我作为导师和临床研究员保持成功所需的持续支持。 公共卫生相关性：肢端肥大症是一种由生长激素产生的垂体瘤引起的罕见疾病，与发病率和死亡率增加有关。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大型、持续的前瞻性肢端肥大症队列研究来描述肢端肥大症的新特征，包括异常的脂肪分布，这可能会导致其发病率和死亡率的增加。我们的研究将带来关于 GH 和 IGF-I 对身体成分、脂肪组织炎症、内皮功能障碍、骨密度和心血管风险的影响的重要知识，这也适用于我们对 GH 使用和过度使用在其他临床环境中的影响的理解。

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.