Integration of Nutritional Metabolomics with Bioenergetics in Cystic Fibrosis

营养代谢组学与生物能量学在囊性纤维化中的整合

• 批准号: 8893079
• 负责人: Jessica Alejandra Alvarez
• 金额: $ 10.71万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8893079
• 关键词: 25-hydroxyvitamin D; Acute; Adult; Affect; Age; American; Antioxidants; Attenuated; Bioenergetics; Caring; Catabolism; Cessation of life; Cholecalciferol; Chronic; Clinical; Clinical Research; Clinical Sciences; Coenzyme A; Collaborations; Comorbidity; Complement; Coupled; Cross-Sectional Studies; Cysteine; Cystic Fibrosis; Cystine; Data; Defect; Diabetes Mellitus; Disease; Disulfides; Doctor of Philosophy; Dose; Double-Blind Method; Educational workshop; Environment; Equilibrium; Fasting; Fatty acid glycerol esters; Functional disorder; Funding; Generations; Glucose; Glutathione; Glutathione Disulfide; Goals; Grant; Health; Hereditary Disease; High Pressure Liquid Chromatography; High Prevalence; Indirect Calorimetry; Infection; Inflammation; Institutes; Laboratories; Lead; Life; Life Expectancy; Lung; Magnetic Resonance Spectroscopy; Maintenance; Malabsorption Syndromes; Measures; Medical; Mentors; Metabolism; Methods; Mission; Muscle function; National Institute of Diabetes and Digestive and Kidney Diseases; Nutrient; Nutritional; Nutritional Study; Nutritional Support; Nutritional status; Oral; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Phosphocreatine; Pilot Projects; Plasma; Play; Process; Pulmonary Cystic Fibrosis; Randomized Controlled Trials; Recovery; Research; Resolution; Resources; Respiratory Failure; Respiratory Muscles; Respiratory physiology; Rest; Risk; Role; Serum; Signal Transduction; Signaling Protein; Site; Skeletal Muscle; Source; Structure; Sulfhydryl Compounds; Supplementation; System; Thigh structure; Time; Training; Translational Research; United States National Institutes of Health; Universities; Vitamin D; Vitamin D Deficiency; Vitamin D2; Work; acylcarnitine; aminothiol; base; career development; cohort; cystic fibrosis patients; design; exhaust; extracellular; fatty acid oxidation; glucose tolerance; improved; in vivo; indexing; insight; liquid chromatography mass spectrometry; metabolomics; multidisciplinary; novel; nutrition; outcome forecast; oxidation; patient population; premature; programs; protein structure function; public health relevance; research and development; skeletal muscle wasting; tool; transcription factor

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：囊性纤维化（CF）是一种分解代谢的隐性遗传疾病，其预后高度依赖于维持足够的营养状态。随着预期寿命的增加，合并症如CF相关糖尿病（CFRD）变得更加普遍。因此，确定病理生理学途径变得越来越重要， 营养疗法对成人CF患者的影响。代谢组学分析的最新进展提供了一个新的机会，广泛探索代谢和相关的疾病恶化和恢复CF的潜在途径。PI，Jessica A。Alvarez，PhD，RD将使用高分辨率液相色谱-质谱（LC-MS）代谢组学方法作为工具，与多学科专家导师团队（包括首席导师托马斯R.齐格勒和共同导师Dean P. Jones博士、Vin Tangpricha博士、Arlene A. Stecenko和Nael A. McCarty）。根据PI和指导团队的初步临床和代谢组学研究结果，该项目的工作假设是：1）CF中的氨基硫醇氧化还原失衡导致脂肪酸氧化受损，2）维生素D补充剂使氧化还原系统正常化，随后，氧化。具体目标1是在一项对成年CF受试者与健康、年龄匹配的对照组进行比较的横断面研究中，使用高分辨率靶向血浆代谢组学分析和补充的体内生物能量评估方法（间接量热法、31磷磁共振光谱法）确认成年CF受试者的β-氧化缺陷。具体目标2将确定血浆氨基硫醇氧化还原状态是否与本横断面研究中的β-氧化相关。具体目标3是一项先导性研究，旨在确定高剂量口服维生素D3对因肺部恶化住院的成人CF患者的β-氧化和氨基硫醇氧化还原指数的影响，并在一项正在进行的双盲随机对照试验中进行临床恢复。埃默里大学拥有一个智力丰富的研究环境，其资源将用于开展拟议的研究，包括NIH资助的亚特兰大临床和转化科学研究所临床研究网络网站。这个K 01职业发展建议的主要目标是让Alvarez博士发展高分辨率代谢组学的专业知识，用于临床营养研究，这将极大地补充她迄今为止的营养和代谢培训。拟议的研究，结合结构化的指导和培训计划，包括教学课程和研讨会，旨在促进阿尔瓦雷斯博士的长期目标，即在慢性分解代谢疾病（如CF）中开发一个独立资助的临床和转化营养研究计划，与NIDDK的使命一致。