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: 8764070
• 负责人: Jessica Alejandra Alvarez
• 金额: $ 10.73万
• 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/8764070
• 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 Acids; 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; 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 β-oxidation, and 2) vitamin D supplementation normalizes the redox system and, subsequently, β-oxidation. Specific Aim 1 is to confirm a defect in β-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 β-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 β-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（由适用提供）：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适当的营养状况。随着预期寿命的增加，诸如CF相关糖尿病（CFRD）等合并症变得更加普遍。因此，识别将告知病理生理途径的病理生理途径越来越重要 成人CF患者的营养疗法。代谢组学分析的最新进展为广泛探索与疾病加剧和康复有关的新陈代谢和潜在途径提供了新的机会。 PI，Jessica A. Alvarez，PhD，RD，将使用高分辨率，液态色谱质量光谱法（LC-MS）代谢组学方法作为一种工具，可以在成人CF患者中询问血浆中的血浆代谢组，与有或没有CFRD的成人CFRD，与多个学科团队合作，包括专家训练者（包括专业人士）。 Dean P. Jones，Vin Tangpricha，Arlene A. Stecenko和Nael A. McCarty）。基于PI和心理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不平衡有助于脂肪酸β-氧化受损，而2）补充维生素D的补充正常使氧化还原系统和后续β-氧化。具体目的1是使用高分辨率靶向血浆代谢组学分析和在体内生物能评估方法（间接热量法，31经磷磷酸谐振光谱镜检查）在成人的成人研究中对CF与CF的成年受试者相比，在成年研究中，证实了成人CF受试者的β氧化缺陷。具体目标2将确定在这项横断面研究中等离子体氨基硫醇氧化还原状态是​​否与β氧化有关。具体目标3是一项初步研究，旨在确定高剂量口服维生素D3对成年CF患者的β-氧化和氨基硫醇氧化还原指数的影响，该患者因肺部加重而住院，并在正在进行的双盲，随机对照试验中临床恢复期间临床恢复。埃默里大学（Emory University）拥有一个智力丰富的研究环境，其资源将用于进行拟议的研究，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站。这项K01职业发展建议的主要目标是，Alvarez博士在临床营养研究中开发高分辨率代谢组学专业知识，这将高度补充她的营养和代谢培训。拟议的研究结合了包括教学课程和讲习班在内的结构化心理和培训计划，旨在促进Alvarez博士的长期目标，即在CF等慢性分解代谢疾病中开发独立资助的临床和翻译营养研究计划，例如CF，与NIDDK的任务一致。