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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01DK102851-01
Application #
8764070
Study Section
Digestive Diseases and Nutrition C Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2014-08-01
Project End
2019-04-30
Budget Start
2014-08-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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
Han, Jenny E; Alvarez, Jessica A; Staitieh, Bashar et al. (2017) Oxidative stress in critically ill ventilated adults: effects of vitamin D3 and associations with alveolar macrophage function. Eur J Clin Nutr :
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
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
Alvarez, Jessica A; Chong, Elizabeth Y; Walker, Douglas I et al. (2017) Plasma metabolomics in adults with cystic fibrosis during a pulmonary exacerbation: A pilot randomized study of high-dose vitamin D3 administration. Metabolism 70:31-41
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
Smith, Ellen M; Jones, Jennifer L; Han, Jenny E et al. (2016) High-Dose Vitamin D3 Administration Is Associated With Increases in Hemoglobin Concentrations in Mechanically Ventilated Critically Ill Adults: A Pilot Double-Blind, Randomized, Placebo-Controlled Trial. JPEN J Parenter Enteral Nutr :
Alvarez, Jessica A; Ziegler, Thomas R; Millson, Erin C et al. (2016) Body composition and lung function in cystic fibrosis and their association with adiposity and normal-weight obesity. Nutrition 32:447-52
Alvarez, Jessica A; Grunwell, Jocelyn R; Gillespie, Scott E et al. (2016) Vitamin D deficiency is associated with an oxidized plasma cysteine redox potential in critically Ill children. J Steroid Biochem Mol Biol :
Lee, Moon Jeong; Alvarez, Jessica A; Smith, Ellen M et al. (2015) Changes in Mineral Micronutrient Status During and After Pulmonary Exacerbation in Adults With Cystic Fibrosis. Nutr Clin Pract 30:838-43

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