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. PROJECT NARRATIVE 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.

Agency
National Institute of Health (NIH)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24DK073040-10
Application #
8704921
Study Section
Digestive Diseases and Nutrition C Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
Reyes-Vidal, Carlos; Fernandez, Jean Carlos; Bruce, Jeffrey N et al. (2014) Prospective study of surgical treatment of acromegaly: effects on ghrelin, weight, adiposity, and markers of CV risk. J Clin Endocrinol Metab 99:4124-32
Geer, Eliza B; Shen, Wei; Strohmayer, Erika et al. (2012) Body composition and cardiovascular risk markers after remission of Cushing's disease: a prospective study using whole-body MRI. J Clin Endocrinol Metab 97:1702-11
Thearle, Marie S; Freda, Pamela U; Bruce, Jeffrey N et al. (2011) Temozolomide (Temodarýý) and capecitabine (Xelodaýý) treatment of an aggressive corticotroph pituitary tumor. Pituitary 14:418-24
Lund, Lars H; Freda, Pamela; Williams, Jill J et al. (2010) Leptin resistance after heart transplantation. Eur J Heart Fail 12:516-20
Reid, Tirissa J; Post, Kalmon D; Bruce, Jeffrey N et al. (2010) Features at diagnosis of 324 patients with acromegaly did not change from 1981 to 2006: acromegaly remains under-recognized and under-diagnosed. Clin Endocrinol (Oxf) 72:203-8
Frystyk, Jan; Freda, Pamela; Clemmons, David R (2010) The current status of IGF-I assays--a 2009 update. Growth Horm IGF Res 20:8-18
Bidlingmaier, Martin; Freda, Pamela U (2010) Measurement of human growth hormone by immunoassays: current status, unsolved problems and clinical consequences. Growth Horm IGF Res 20:19-25
Lund, Lars H; Freda, Pamela; Williams, Jill J et al. (2009) Growth hormone resistance in severe heart failure resolves after cardiac transplantation. Eur J Heart Fail 11:525-8
Lund, Lars H; Williams, Jill J; Freda, Pamela et al. (2009) Ghrelin resistance occurs in severe heart failure and resolves after heart transplantation. Eur J Heart Fail 11:789-94
Freda, Pamela U (2009) Monitoring of acromegaly: what should be performed when GH and IGF-1 levels are discrepant? Clin Endocrinol (Oxf) 71:166-70

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