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

基本信息

批准号：
9259968
负责人：
Jessica Alejandra Alvarez
金额：
$ 14.62万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/9259968
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 Impairment 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 Oxides 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 Site Skeletal Muscle Source Structure Sulfhydryl Compounds System Thigh structure Time Training Translational Research United States National Institutes of Health Universities Vitamin D Vitamin D Deficiency Vitamin D supplementation 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 metabolome metabolomics multidisciplinary novel nutrition outcome forecast oxidation patient population premature programs protein function protein structure public health relevance recessive genetic trait research and development skeletal muscle wasting tool transcription factor

项目摘要

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）是一种分解代谢性隐性遗传病，其预后高度依赖于维持足够的营养状态。随着预期寿命的延长，囊性纤维化（CF）相关糖尿病（CFRD）等合并症变得越来越多。因此，确定可以提供信息的病理生理学途径变得越来越重要。代谢组学分析的最新进展为广泛探索与 CF 疾病恶化和恢复相关的代谢和潜在途径提供了新的机会。 , 液相色谱-质谱 (LC-MS) 代谢组学方法作为一种工具，与患有或不患有 CFRD 的成年 CF 患者队列中的代谢组学相关多学科专家导师团队（包括首席导师 Thomas R. Ziegler 博士和联合导师 Dean P. Jones、Vin Tangpricha、Arlene A. Stecenko 和 Nael A. McCarty 博士）基于初步临床和代谢组学研究结果。 PI和指导团队，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）补充维生素D使氧化还原系统正常化，随后进行 β-氧化特定目标 1 是使用高分辨率靶向血浆代谢组学分析和补充体内生物能评估方法（间接量热法、31磷磁法）确认成人 CF 受试者的 β-氧化缺陷。共振光谱）在成年 CF 受试者与健康、年龄匹配对照的横断面研究中，特定目标 2 将确定血浆氨基硫醇氧化还原状态。在这项横断面研究中，特定目标 3 是一项初步研究，旨在确定高剂量口服维生素 D3 对因肺部病情加重住院并随访的成年 CF 患者的 β-氧化和氨基硫醇氧化还原指标的影响。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，包括美国国立卫生研究院资助的亚特兰大临床和临床恢复期间。转化科学研究所临床研究网络网站的主要目标是让 Alvarez 博士发展高分辨率代谢组学方面的专业知识，用于临床导向的营养研究，这将极大地补充她迄今为止的营养和代谢培训。拟议的研究与包括教学课程和研讨会在内的结构化指导和培训计划相结合，旨在促进阿尔瓦雷斯博士的长期目标，即开发一个独立资助的慢性病临床和转化营养研究项目。分解代谢疾病，例如 CF，与 NIDDK 的使命一致。