Cystic fibrosis (CF) is a catabolic, recessive genetic disease whose prognosis is highly dependent on maintenance of adequate nutritional status. As life expectancy increases, co-morbidities such as CF-related diabetes (CFRD) become more prevalent. It is thus increasingly important to identify pathophysiologic pathways that will inform nutritional therapies for adult patients with CF. Recent advances in metabolomics analysis provide a novel opportunity to broadly explore metabolism and underlying pathways relevant to disease exacerbation and recovery in CF. The PI, Jessica A. Alvarez, PhD, RD, will use high-resolution, liquid chromatography-mass spectrometry (LC-MS) metabolomics methods as a tool to interrogate the plasma metabolome in cohorts of adult CF patients, with or without CFRD, in collaboration with a multidisciplinary team of expert mentors (including Lead Mentor Dr. Thomas R. Ziegler and Co-Mentors Drs. Dean P. Jones, Vin Tangpricha, Arlene A. Stecenko, and Nael A. McCarty). Based on preliminary clinical and metabolomics research findings by the PI and the mentoring team, the working hypotheses of this project are: 1) aminothiol redox imbalance in CF contributes to impaired fatty acid ?-oxidation, and 2) vitamin D supplementation normalizes the redox system and, subsequently, ?-oxidation.
Specific Aim 1 is to confirm a defect in ?-oxidation in adult CF subjects using high-resolution targeted plasma metabolomics analysis and complementary in vivo bioenergetic assessment methods (indirect calorimetry,31phosphorus-magnetic resonance spectroscopy) in a cross-sectional study of adult subjects with CF compared to healthy, age matched controls.
Specific Aim 2 will determine if plasma aminothiol redox status is associated with ?-oxidation in this cross-sectional study.
Specific Aim 3 is a pilot study to determine the impact of high-dose oral vitamin D3 on indexes of ?-oxidation and aminothiol redox in adult CF patients hospitalized for pulmonary exacerbation and followed during clinical recovery in an ongoing, double-blind, randomized controlled trial. Emory University boasts an intellectually rich research environment whose resources will be used to carry out the proposed research, including an NIH-funded Atlanta Clinical and Translational Science Institute Clinical Research Network site. The primary goal of this K01 career development proposal is for Dr. Alvarez to develop expertise in high-resolution metabolomics for use in clinically oriented nutrition research, which will highly complement her nutrition and metabolism training to-date. The proposed research, in combination with a structured mentoring and training plan that includes didactic courses and workshops, is designed to facilitate Dr. Alvarez's long-term goal of developing an independently-funded clinical and translational nutrition research program in chronic catabolic diseases, such as CF, consistent with the mission of the NIDDK.
With better medical care, patients with cystic fibrosis, a life-threatening disease, are enjoying longer lives. Nutrition plays a major role in maintaining optimal health in cystic fibrosis. This project is designed to investigate nutrition-related factors, such s vitamin D status, on oxidative stress and fat oxidation which may influence long-term survival in cystic fibrosis.
|Alvarez, Jessica A; Grunwell, Jocelyn R; Gillespie, Scott E et al. (2018) Vitamin D deficiency is associated with an oxidized plasma cysteine redox potential in critically Ill children. J Steroid Biochem Mol Biol 175:164-169|
|Bettermann, Erika L; Hartman, Terryl J; Easley, Kirk A et al. (2018) Higher Mediterranean Diet Quality Scores and Lower Body Mass Index Are Associated with a Less-Oxidized Plasma Glutathione and Cysteine Redox Status in Adults. J Nutr 148:245-253|
|Han, Jenny E; Alvarez, Jessica A; Staitieh, Bashar et al. (2018) Oxidative stress in critically ill ventilated adults: effects of vitamin D3 and associations with alveolar macrophage function. Eur J Clin Nutr 72:744-751|
|Roshanravan, Baback; Zelnick, Leila R; Djucovic, Daniel et al. (2018) Chronic kidney disease attenuates the plasma metabolome response to insulin. JCI Insight 3:|
|Kanhere, Mansi; He, Jiabei; Chassaing, Benoit et al. (2018) Bolus Weekly Vitamin D3 Supplementation Impacts Gut and Airway Microbiota in Adults With Cystic Fibrosis: A Double-Blind, Randomized, Placebo-Controlled Clinical Trial. J Clin Endocrinol Metab 103:564-574|
|Han, Jenny E; Alvarez, Jessica A; Jones, Jennifer L et al. (2017) Impact of high-dose vitamin D3 on plasma free 25-hydroxyvitamin D concentrations and antimicrobial peptides in critically ill mechanically ventilated adults. Nutrition 38:102-108|
|Cai, Qingpo; Alvarez, Jessica A; Kang, Jian et al. (2017) Network Marker Selection for Untargeted LC-MS Metabolomics Data. J Proteome Res 16:1261-1269|
|Smith, Ellen M; Alvarez, Jessica A; Kearns, Malcolm D et al. (2017) High-dose vitamin D3 reduces circulating hepcidin concentrations: A pilot, randomized, double-blind, placebo-controlled trial in healthy adults. Clin Nutr 36:980-985|
|Hermes, Wendy A; Alvarez, Jessica A; Lee, Moon J et al. (2017) Prospective, Randomized, Double-Blind, Parallel-Group, Comparative Effectiveness Clinical Trial Comparing a Powder Vehicle Compound of Vitamin D With an Oil Vehicle Compound in Adults With Cystic Fibrosis. JPEN J Parenter Enteral Nutr 41:952-958|
|Tangpricha, Vin; Smith, Ellen M; Binongo, Jose et al. (2017) The Vitamin D for Enhancing the Immune System in Cystic Fibrosis (DISC) trial: Rationale and design of a multi-center, double-blind, placebo-controlled trial of high dose bolus administration of vitamin D3 during acute pulmonary exacerbation of cystic fib Contemp Clin Trials Commun 6:39-45|
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