Integration of Nutritional Metabolomics with Bioenergetics in Cystic Fibrosis

描述(申请人提供)：囊性纤维化(CF)是一种分解代谢、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，合并疾病，如慢性阻塞性肺疾病相关糖尿病(CFRD)变得更加普遍。因此，确定病理生理途径就变得越来越重要 成人CF患者的营养治疗。代谢组学分析的最新进展提供了一个新的机会，广泛地探索与疾病恶化和恢复相关的代谢和潜在途径。PIE，Jessica A.Alvarez，Phd，RD，将使用高分辨率高效液-质联用(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Thomas R.Ziegler博士和共同导师Dean P.Jones博士、Vin Tangpricha博士、Arlene A.Stecenko博士和Nael A.McCarty)合作，询问患有或不患有CFRD的成年CF患者的血浆代谢组。基于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受损的脂肪酸β氧化，以及2)补充维生素D使氧化还原系统正常化，从而导致β氧化。具体目标1是利用高分辨率靶向血浆代谢组学分析和体内补充生物能量评估方法(间接量热法，31P-磁共振波谱)，以年龄匹配的健康对照组为对照，对成年CF受试者进行横断面研究，以确认成年CF受试者的β氧化缺陷。在这项横断面研究中，特定目标2将确定血浆氨基硫醇氧化还原状态是否与β氧化有关。具体目标3是一项正在进行的双盲随机对照试验，旨在确定大剂量口服维生素D3对因肺加重而住院并在临床康复期间接受随访的成年CF患者的β氧化和氨基硫醇氧化还原指标的影响。埃默里大学拥有丰富的智力研究环境，其资源将用于开展拟议的研究，包括由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。这份K01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的营养和新陈代谢培训。这项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，即根据NIDDK的使命，开发一个独立资助的慢性分解代谢性疾病(如CF)的临床和转化性营养研究计划。

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.