Patients with cystic fibrosis (CF) are at risk for endocrine complications of their disease, including osteoporosis and diabetes. These complications are associated with significant morbidity and mortality in this patient population, and the underlying pathogenesis is not well understood. Recent evidence suggests that the CF transmembrane conductance regulator (CFTR) protein is expressed in human bone cells and pancreatic beta cells and may play a causative role in these disorders. A new FDA-approved medication, ivacaftor, pharmacologically potentiates CFTR activity in subjects with G551D-CFTR mutations and has been shown to improve pulmonary function and sweat chloride levels. This medication offers the unique opportunity to study the effects of improving CFTR function on bone and glucose homeostasis in humans with CF. This project is a prospective multiple cohort study, conceived and developed solely by the candidate under the guidance of her mentors, with goals to (1) investigate the effect of G551D genotype on the development of endocrine complications of CF; (2) assess change in (a) bone microarchitecture and volumetric bone mineral density using state-of-art skeletal imaging techniques and (b) measures of glucose homeostasis in subjects treated with ivacaftor compared to CF patients not receiving this medication and healthy subjects matched for age, race, and gender; and (3) investigate a bone-derived protein, undercarboxylated osteocalcin, as a novel mechanism linking CF-related bone disease and CF-related diabetes. Dr. Putman is a dual-trained adult and pediatric endocrinologist whose ultimate career goal is to become a successful, independent clinical investigator in the field of CF-related endocrine complications. During the time period of her K23 grant, she will acquire the requisite skills in clinical and translational investigation through a detailed career development plan that consists of formal course work, attendance of conferences and seminars, participation in workshops, and hands-on experience specifically in the areas of (1) endocrinology, including bone health and diabetes, (2) CF, and (3) clinical research. She will be mentored by leading investigators in the field of bone and mineral metabolism (Drs. Finkelstein and Bouxsein) and CF (Dr. Moskowitz), all of whom have considerable mentoring experience. Her advisory committee will include a team of distinguished experts in the fields of pediatric bone health, osteoporosis, CF, and diabetes. In summary, the research and mentoring plan proposed in this K23 application will test innovative hypotheses about the role of CFTR in bone and glucose homeostasis, will broaden our understanding of the endocrine complications of CF, and will provide the necessary training and investigational niche for Dr. Putman to develop a successful, independent career in clinical research.

Public Health Relevance

Recent studies suggest that cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in bone and pancreatic beta cells and may play a role in the cystic fibrosis (CF) related bone disease and CF-related diabetes (CFRD). The goal of this study is to determine if CFTR potentiation with a new FDA-approved medication, ivacaftor, improves bone density and glucose homeostasis in CF patients, thereby improving our understanding and treatment of these CF-related endocrine complications. In addition, the study will offer the opportunity to characterize in detail a subset of patients with a specific CF genotype (G551D-CFTR mutations), as well as explore novel mechanisms linking the bone disease and glucose abnormalities observed in patients with CF.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mentored Patient-Oriented Research Career Development Award (K23)
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Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
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Spain, Lisa M
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Boston Children's Hospital
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Putman, Melissa S; Simoneau, Tregony; Feldman, Henry A et al. (2018) Low bone density and fractures before and after pediatric lung transplantation. Bone 111:129-134
Putman, Melissa S; Haagensen, Alexandra; Neuringer, Isabel et al. (2017) Celiac Disease in Patients with Cystic Fibrosis-Related Bone Disease. Case Rep Endocrinol 2017:2652403
Putman, Melissa S; Yu, Elaine W; Lin, David et al. (2017) Differences in Trabecular Microstructure Between Black and White Women Assessed by Individual Trabecular Segmentation Analysis of HR-pQCT Images. J Bone Miner Res 32:1100-1108
Putman, M S; Greenblatt, L B; Sicilian, L et al. (2016) Young adults with cystic fibrosis have altered trabecular microstructure by ITS-based morphological analysis. Osteoporos Int 27:2497-505