Mechanisms of Carotenoid Transport and Interactions with Nutrient Absorption

类胡萝卜素运输机制及其与营养吸收的相互作用

• 批准号: 8805024
• 负责人: Nancy E Moran
• 金额: $ 9.04万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8805024
• 关键词: ATP binding cassette transporter 1; Advisory Committees; Affect; American; Analytical Chemistry; Animal Model; Animals; Award; Belief; Benefits and Risks; Bioavailable; Biodistribution; Biological; Biological Availability; Biometry; Blood; CD36 gene; Caco-2 Cells; Cardiovascular Diseases; Carotene; Carotenoids; Carrier Proteins; Cell Culture Techniques; Cell physiology; Cells; Chemistry; Chronic Disease; Clinic; Clinical Research; Clinical Trials; Clinical Trials Design; Complex; Consumption; Cre-LoxP; Development; Development Plans; Diet; Dietary Carotenoid; Dietary Intervention; Dietary Phytochemical; Dose; Drug or chemical Tissue Distribution; Eating; Environment; Epidemiologist; Epidemiology; Epithelial; Faculty; Food; Food Interactions; Foundations; Future; Genes; Genetic; Genetic Variation; Genetic study; Goals; Health; Health Benefit; Health Personnel; Heterogeneity; Human; In Vitro; Individual; Intention; Interdisciplinary Study; Intervention Studies; Interview; Intestinal Absorption; Intestines; Investigation; Isotope Labeling; Job Application; Kinetics; Knockout Mice; Label; Lead; Lipids; Lutein; Malignant Neoplasms; Mediating; Mediation; Medical Genetics; Medical center; Membrane Transport Proteins; Mentors; Metabolic; Methods; Minor; Modeling; Molecular Genetics; Molecular and Cellular Biology; Myocardial Infarction; Nutrient; Nutritional; Nutritional Biochemistry; Nutritional Science; Nutritional Study; Nutritionist; Occupations; Ohio; Oral; Peer Review; Persons; Phase; Physicians; Physiological; Phytochemical; Pigments; Plants; Plasma; Population Study; Powder dose form; Preparation; Prevention Research; Process; Production; Prostate; Prostatic; Proteins; Public Health; Radioisotopes; Recommendation; Relative (related person); Reporting; Research; Research Training; Risk; Risk Reduction; Rodent; Role; Scientist; Serum; Site; Stroke; Structure; Testing; Time; Tissues; Tocopherols; Tomatoes; Tracer; Training; Translating; Universities; Vision; Vitamin A; Vitamin E; Wild Type Mouse; absorption; cardiovascular disorder risk; career; career development; cohort; collaborative environment; college; design; dietary supplements; disorder prevention; disorder risk; evidence based guidelines; experience; feeding; food science/technology; functional food; gene interaction; genome wide association study; in vitro Model; lipid transport; lycopene; malignant breast neoplasm; meetings; metabolic abnormality assessment; mouse model; nutrient absorption; nutrition; nutrition related genetics; phytoene; pi bond; post-doctoral training; professor; programs; response; stable isotope; tool; uptake

DESCRIPTION (provided by applicant): Candidate: I am a trained, translational nutrition scientist focused on investigating the complex nutrigenetic and nutritional factors that impact physiological responses to dietary interventions. With a foundation in Molecular and Cellular Biology and Chemistry, I first began studying the nutritional aspects of dietary phytochemicals by developing in vitro plant cell culture methods for production of isotope-labeled phytochemical tracers for rodent metabolic studies. During my doctoral training in Nutritional Sciences, I extended this paradigm for production of both stable isotope- and radioisotope-labeled tomato carotenoids, and studied the kinetics and distribution of unlabeled tomato carotenoids in animal models, leading to 3 firstauthored and 2 co-authored, peer-reviewed articles. During my postdoctoral training, I first-authored 4 and coauthored 4 research and review articles. I translated and utilized the tracer tools I previously developed, for animal and human metabolic investigation, and found that, even in controlled conditions, human kinetic responses to the red tomato carotenoid, lycopene (associated with a reduced risk of several chronic diseases and malignancies), vary widely. Furthermore, I found the kinetics of lycopene and a structurally similar, potentially bioactive tomato carotenoid, phytoene, to differ markedly, with phytoene being 3-times more bioavailable and more slowly cleared from the plasma and tissues. This partially explained why phytoene, although a minor carotenoid in tomatoes (~17% the level of lycopene), is a major carotenoid in the body. Research: To understand the cause of heterogeneous responses to diet and to devise strategies to enhance bioavailability or target tissue distribution, we must define the mechanisms of carotenoid cellular uptake and efflux. Phytoene and lycopene are a compelling pair to study, as their bioavailability and biodistribution differ markedly, and both likely contribute to the many health benefits of tomato consumption including a decreased risk of several cancers and cardiovascular disease. Recent, genome-wide association and mechanistic studies suggest cellular lipid transporters are associated with carotenoid status, yet how these transporters relate to lycopene and phytoene uptake and distribution is poorly understood. We propose to study the interactions between phytoene and lycopene with associated transport proteins, which lead to differences in bioavailability and distribution, and to determine how these carotenoids may interact with the absorption of other nutritional compounds sharing the same transporters. Aim 1. To determine if intestinal absorption and prostatic uptake and efflux of phytoene and lycopene is mediated by any of 3 (SCARB1, CD36, or ABCA1) candidate lipid transporters in in vitro models. Aim 2. To define the physiological contribution of lipid transporters (SCARB1, CD36, and ABCA1&G1) to lycopene and phytoene absorption and systemic distribution using knockout mice. Aim 3. To determine if and how lycopene or phytoene impact absorption of two phytonutrients, ß-carotene (pro-vitamin A) and α-tocopherol (vitamin E), which are known to be transported by SCARB1 & CD36. Research career development plan: I have a strong background in nutrition, analytical chemistry, and phytochemical kinetics. Award of the K99 will allow me to expand my research experience to include mechanistic, genetic investigations of complex, gene:phytochemical interactions. This experience would center on the use of in vitro and genetic mouse models to study the function of lipid transport proteins in carotenoid absorption. The co-mentors, Steven Clinton and Earl Harrison, are leaders in the fields of translational nutrition research for disease prevention and carotenoid nutritional biochemistry, respectively, making them ideal mentors for the proposed K99 phase and for my transition to a career in phytochemical-nutrigenetic research. I will interact with my mentors weekly at research meetings, but will also interact with an advisory committee, which will meet semi-annually to formally evaluate my training and research progress. The committee consists of professors from the departments of Food Science & Technology, Medical Genetics, and Biostatistics, and will provide guidance both on the scientific rigor of the K99 research, but also on my preparation for faculty job applications, practice interviews, and job negotiations, to assure my successful transition. Environment: The Ohio State University and Wexner Medical Center is a remarkably rich environment for interdisciplinary nutrition and disease prevention research. OSU's "Crops to the Clinic" program spans three colleges and promotes a multi-level, interdisciplinary research program in which plant scientists, food scientists, basic and applied nutritionists, epidemiologists, and physicians collaborate to study the kinetics and bioactivities of dietary compounds and functional foods. Long-term career goals: My long-term goals are to A) establish an academic lab at a research university to conduct cutting-edge studies of dietary bioactive compound nutrigenetics, kinetics, and bioactivities, to B) train future leaders in the field of dietary bioactive compounds and nutrigenetics, and to C) promote rigorous investigations of dietary phytochemicals for evidence-based recommendations on diet and supplement use. Impact: By unraveling the gene:phytochemical and nutrient:phytochemical factors impacting the response to diet, we will be able to design well-informed clinical trials and to develop public health diet and supplement use recommendations to maximize benefits and minimize risks. The training plan is designed for me to become a highly trained, interdisciplinary, translational nutrition scientist who is uniquely prepared to meet this challenge.

候选人：我是一名训练有素的转化营养科学家，专注于研究影响饮食干预生理反应的复杂营养和营养因素。在分子和细胞生物学和化学的基础上，我首先开始研究膳食植物化学的营养方面，通过开发体外植物细胞培养方法来生产同位素标记的植物化学示踪剂，用于啮齿动物的代谢研究。在营养科学博士培训期间，我将这种模式扩展到稳定同位素和放射性同位素标记的番茄类胡萝卜素的生产，并研究了未标记的番茄类胡萝卜素在动物模型中的动力学和分布，发表了3篇第一作者和2篇合著的同行评审文章。在我的博士后培训期间，我发表了4篇第一作者和合作作者的研究和评论文章。我翻译并利用了我之前开发的示踪工具，用于动物和人类代谢调查，发现即使在受控条件下，人类对红番茄类胡萝卜素，番茄红素（与降低几种慢性疾病和恶性肿瘤的风险有关）的动力学反应差异很大。此外，我发现番茄红素和一种结构相似、具有潜在生物活性的番茄类胡萝卜素——植物烯的动力学显著不同，其中植物烯的动力学是番茄红素的3倍