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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

基本信息

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
项目类别：
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

项目摘要

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.

描述（由申请人提供）：候选人：我是一名训练有素的翻译营养科学家，专注于调查影响饮食干预生理反应的复杂营养遗传和营养因素。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物质的营养方面，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，用于啮齿动物代谢研究。在我的营养科学博士培训期间，我扩展了这种生产稳定同位素和放射性同位素标记的番茄类胡萝卜素的范例，并研究了动物模型中未标记的番茄类胡萝卜素的动力学和分布，导致3首着和2合著，同行评议的文章。在我的博士后培训期间，我首次撰写了4篇研究和评论文章。我翻译并利用我以前开发的示踪工具，用于动物和人类代谢研究，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（与几种慢性疾病和恶性肿瘤的风险降低有关）的动力学反应也有很大差异。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--八氢番茄红素的动力学明显不同，八氢番茄红素是番茄红素的3倍多。生物可利用的和更缓慢地从血浆和组织中清除。这部分解释了为什么八氢番茄红素虽然是番茄中的次要类胡萝卜素（约为番茄红素水平的17%），但却是体内主要的类胡萝卜素。研究：为了了解对饮食的异质性反应的原因，并设计策略来提高生物利用度或靶组织分布，我们必须确定类胡萝卜素细胞摄取和流出的机制。八氢番茄红素和番茄红素是值得研究的一对，因为它们的生物利用度和生物分布显著不同，两者都可能有助于番茄消费的许多健康益处，包括降低患多种癌症和心血管疾病的风险。最近，全基因组关联和机制研究表明，细胞脂质转运蛋白与类胡萝卜素的状态，但这些转运蛋白如何涉及番茄红素和八氢番茄红素的吸收和分布知之甚少。我们建议研究八氢番茄红素和番茄红素与相关转运蛋白之间的相互作用，从而导致生物利用度和分布的差异，并确定这些差异是如何产生的。类胡萝卜素可与共享相同转运蛋白的其它营养化合物的吸收相互作用。目标1.在体外模型中确定八氢番茄红素和番茄红素的肠吸收和前列腺摄取和流出是否由3种候选脂质转运蛋白（SCARB 1、CD 36或ABCA 1）中的任一种介导。目标2.使用基因敲除小鼠确定脂质转运蛋白（SCARB 1、CD 36和ABCA 1和G1）对番茄红素和八氢番茄红素吸收和全身分布的生理作用。目标3.确定番茄红素或八氢番茄红素是否以及如何影响两种植物营养素的吸收，即β-胡萝卜素（维生素A原）和α-生育酚（维生素E），这两种植物营养素已知由SCARB 1和CD 36运输。研究职业发展计划：我在营养学，分析化学和植物化学动力学方面有很强的背景。获得K99奖将使我能够扩展我的研究经验，包括对复杂的基因：植物化学相互作用的机制、遗传学研究。这方面的经验将集中在体外和遗传小鼠模型的使用，以研究脂质转运蛋白在类胡萝卜素吸收中的功能。共同导师，史蒂芬·克林顿和厄尔·哈里森，分别是疾病预防和类胡萝卜素营养生物化学转化营养研究领域的领导者，使他们成为拟议的K99阶段和我向植物化学营养遗传学研究过渡的理想导师。我每周都会在研究会议上与我的导师互动，但也会与咨询委员会互动，每半年开一次会，正式评估我的训练和研究进展。该委员会由来自食品科学与技术，医学遗传学和生物统计学系的教授组成，并将为K99研究的科学严谨性提供指导，同时也为我准备教师工作申请，实践面试和工作谈判提供指导，以确保我成功过渡。工作环境：俄亥俄州州立大学和韦克斯纳医学中心是一个非常丰富的跨学科营养和疾病预防研究的环境。俄勒冈州立大学的“作物到诊所”计划跨越三个学院，促进多层次，跨学科的研究计划，其中植物科学家，食品科学家，基础和应用营养学家，流行病学家和医生合作研究膳食化合物和功能性食品的动力学和生物活性。长期职业目标：我的长期目标是A）在研究型大学建立一个学术实验室，进行饮食生物活性化合物营养遗传学，动力学和生物活性的前沿研究，B）培养饮食生物活性化合物和营养遗传学领域的未来领导者，并C）促进饮食植物化学物质的严格调查，以提供基于证据的饮食和补充剂使用建议。影响：通过揭示影响饮食反应的基因：植物化学和营养素：植物化学因素，我们将能够设计出充分知情的临床试验，并制定公共卫生饮食和补充剂使用建议，以最大限度地提高效益并最大限度地降低风险。培训计划旨在让我成为一名训练有素的跨学科翻译营养科学家，为迎接这一挑战做好了独特的准备。