Role of visceral adipose tissue in frailty among patients with Idiopathic Pulmonary Fibrosis

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PROJECT SUMMARY/ABSTRACT In this application for a 5-year K23 Career Development Award, I propose mentored research and career development leading to a career as an independent clinical and translational investigator in interstitial lung disease (ILD). The goal of this project is to identify the role of body composition in frailty among subjects with idiopathic pulmonary fibrosis (IPF). The prevalence of IPF is rising, currently affecting 1 in 200 older adults. There is no cure for IPF. The only available medications slow disease progression but do not reverse disease. Frailty affects up to 50% of IPF patients, and is characterized by decreased physiologic reserve and increased susceptibility to severe manifestations of acute insults. The most common causes of death in IPF are acute insults. Frailty is thus a potentially modifiable risk factor for morbidity and mortality in IPF. This proposal builds on my preliminary work showing that (1) greater visceral adipose tissue (VAT) is associated with increased frailty, (2) subjects with both sarcopenia and visceral obesity are at greater risk of frailty than those with sarcopenia alone, (3) there may be distinct endotypes of exercise limitation defined by high inflammation alone or low inflammation with high VAT, and (4) down-regulation of the growth hormone (GH) axis may link VAT and frailty. Under the mentorship of Dr. R Graham Barr, I propose to evaluate the roles of body composition by bioelectrical impedance assay (co-mentor Gallagher), inflammation, and neuroendocrine dysregulation associated with frailty risk using a machine-learning approach (co-mentor Valeri). I will also evaluate the role of growth hormone axis dysregulation in sarcopenia with visceral obesity in a rigorous overnight protocol (co-mentor Freda). I propose to perform this in two NHLBI-funded prospective cohorts: Dr. Garcia’s Families-At-Risk for ILD (R01HL103676) and Dr. Singer’s Advanced Lung Disease Lung Transplantation Study (R01HL134851). With guidance from my mentors, I have crafted a 5-year career development plan that includes training in body composition analysis (Dr. Gallagher), measurement of complex endocrine systems (Dr. Freda), clinical trials (Dr. Freda), biostatistics (Dr. Valeri), aging in interstitial lung disease (Dr. Garcia), and epidemiology (Dr. Barr). In the last two years of this award, I will apply for R01 funding and transition to independence. The proposed activities will prepare me to conduct patient-oriented research to evaluate the role of body composition in outcomes in ILD. I will also acquire the skills and training required to design and conduct clinical trials targeting novel pathways to prevent and treat frailty in ILD.