New Approaches to the Evaluation and Treatment of Acromegaly

肢端肥大症评估和治疗的新方法

• 批准号: 7989255
• 负责人: PAMELA U FREDA
• 金额: $ 16.22万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7989255
• 关键词: Accounting; Acromegaly; Adipose tissue; Affect; Aftercare; Architecture; Award; Biochemical; Biological Assay; Biopsy; Blood Circulation; Body Composition; Bone Density; Cardiovascular system; Cell physiology; Clinical; Clinical Research; Cohort Studies; Data; Deposition; Desire for food; Development; Diabetes Mellitus; Disease; Dual-Energy X-Ray Absorptiometry; Endocrine; Endothelial Cells; Energy Metabolism; Ensure; Environment; Etiology; Evaluation; Fatty acid glycerol esters; Fracture; Functional disorder; Funding; Future; Goals; Hepatic; Hormones; Infiltration; Inflammation; Insulin Resistance; Insulin-Like Growth Factor I; Investigation; Knowledge; Lead; Link; Lipids; Lipodystrophy; Lipolysis; Liver; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Medical; Mentors; Metabolic; Metabolic syndrome; Metabolism; Methods; Mid-Career Clinical Scientist Award (K24); Minerals; Morbidity - disease rate; Morphologic artifacts; Muscle; Obesity; Outcome; Patients; Pattern; Peripheral; Pituitary Neoplasms; Play; Postoperative Period; Prevalence; Prospective Studies; Protons; Rare Diseases; Recovery; Research; Research Personnel; Resolution; Risk; Risk Marker; Role; Serum; Serum Markers; Skeleton; Somatotropin; Spinal Fractures; Techniques; Testing; Training; United States National Institutes of Health; Visceral; Weight Gain; Work; X-Ray Computed Tomography; adipokines; base; bone; bone metabolism; bone turnover; cardiovascular risk factor; clinically significant; cohort; experience; ghrelin; improved; increased appetite; indexing; inflammatory marker; insulin sensitivity; macrophage; meetings; metabolomics; mortality; novel; novel strategies; patient oriented; patient oriented research; programs; prospective; public health relevance; subcutaneous; success

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.

描述（由申请人提供）：该项目的总体目标是支持我作为独立面向患者的研究者和成功导师的持续专业发展。我的研究重点是基于高度敏感的GH和IGF-I测量值，建立和验证了厄运式治疗的最佳生化终点，该终点是使用我确定的独特的患者进行的。现在，我们还评估了肢端肥大疗法的临床终点。这项最近的工作确定了肢端肥大症患者的身体成分的新变化。这些发现使我们假设GH-IGF-I过多的特异性脂肪组织（AT）和脂肪营养不良发生，其特征是中心降低，但在肌肉中增加了中心，并且可能导致胰岛素抵抗和心血管造成的风险增加。肢端肥大的治疗可能会扭转这种脂肪营养不良，但是在某些患者中，这可能会增加商店的中心，从而增加AT和循环中的炎症。该应用程序的第四个科学目的是由我的R01 DK064720资助，测试了脂肪营养不良及其恢复在炎症，脂肪因子，食欲激素，内皮功能，CV风险标记和长期结果在炎症时如何影响。我们将利用新颖的技术来进行厄运式研究，包括MR光谱法检查肌肉脂质，脂肪组织用于巨噬细胞浸润和炎症和内皮细胞，用于内皮功能障碍的标志物。了解这种脂肪营养不良及其逆转的后果至关重要，因为它们可能具有长期的临床意义。这项研究是由NIH资助的唯一一项关于肢端肥大的研究，它将提供新颖的重要数据，这也适用于我们对其他临床环境中GH使用和过度使用的影响的理解。该应用程序包括对GH/IGF-I过度及其对骨骼的治疗的影响（AIM 5）。肢端肥大症的骨折增加，但骨矿物质密度（BMD）并未减少。使用HRPQCT对骨骼结构进行新的评估，如果骨骼结构（通过HRPQCT）受损，我们将确定骨骼结构（由于骨骼大小增加的骨骼造成的骨骼，骨骼结构受损，我们将确定骨骼结构（通过HRPQCT）受损，我们将确定骨骼结构（由HRPQCT）受损，我们将确定。我的生产力，正在进行的NIH资助的临床研究计划，成功的指导记录以及我在以患者为导向的研究方面的16年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维持对NIH资助的以患者为导向的研究和指导的高度努力。没有它，我的临床和行政职责将大大增加，而对当前和未来的受训者的培训有害。哥伦比亚的机构环境具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，非常适合吸引研究员并进行我们的研究。续签该奖项是确保我继续作为导师和临床研究人员取得成功所需的支持的理想机制。 公共卫生相关性：由于产生垂体肿瘤的生长激素而引起的一种罕见疾病，与发病率和死亡率增加有关。在这个项目中，我们将利用现代化的生化方法，新颖的技术以及一个独特的，持续的前瞻性肢端肥大队列研究来表征肢端肥大的新特征，包括异常脂肪分布，可能会对其发病率提高和死亡率产生重大贡献。我们的研究将导致有关GH和IGF-I对人体组成，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，这也适用于我们对其他临床环境中GH使用和过度使用的影响的理解。