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.

描述（由申请人提供）： 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遗传和营养因素，凭借分子和细胞生物学和化学的基础，我首先开始研究。通过开发体外植物细胞培养方法来生产用于啮齿动物代谢研究的同位素标记植物化学示踪剂，研究膳食植物化学物质的营养方面。在我的营养科学博士培训期间，我扩展了这一点。在我的博士后培训期间，我开发了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范例，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，从而发表了 3 篇第一作者和 2 篇共同作者的同行评审文章。第一作者 4 篇，共同撰写 4 篇研究和评论文章，我翻译并利用了我之前开发的追踪工具，用于动物和人类代谢研究，并发现，即使在在受控条件下，人类对红色番茄类胡萝卜素番茄红素（与降低多种慢性疾病和恶性肿瘤风险相关）的动力学反应差异很大。此外，我发现番茄红素和结构相似、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反应差异很大。差异显着，八氢番茄红素是其三倍多 这部分解释了为什么八氢番茄红素虽然是番茄中的一种次要类胡萝卜素（约为番茄红素水平的 17%），但却是体内的一种主要类胡萝卜素。 研究：了解异质反应的原因。为了控制饮食并制定增强生物利用度或目标组织分布的策略，我们必须明确类胡萝卜素细胞摄取和流出的机制。番茄是值得研究的一对，因为它们的生物利用度和生物分布显着不同，并且两者都可能有助于食用番茄的许多健康益处，包括降低多种癌症和心血管疾病的风险。最近的全基因组关联和机制研究表明细胞脂质转运蛋白。与类胡萝卜素状态相关，但这些转运蛋白与番茄红素和八氢番茄红素的吸收和分布之间的关系却知之甚少，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。这导致了生物利用度和分布的差异，并确定这些差异如何 类胡萝卜素可能与共享相同转运蛋白的其他营养化合物的吸收相互作用。 目的 1. 确定八氢番茄红素和番茄红素的肠道吸收以及前列腺摄取和流出是否由 3 种候选脂质转运蛋白（SCARB1、CD36 或 ABCA1）中的任何一种介导。目标 2. 确定脂质转运蛋白（SCARB1、CD36 和 ABCA1&G1）对使用基因敲除小鼠研究番茄红素和八氢番茄红素的吸收和全身分布。 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 β-胡萝卜素（维生素原 A）和 α-生育酚（维生素 E）的吸收。由SCARB1和CD36输送 研究职业发展计划：我在营养学、分析化学和植物化学方面有很强的背景。 K99 奖将使我能够扩展我的研究经验，包括复杂的基因：植物化学相互作用的机制、遗传研究。这种经验将集中于使用体外和遗传小鼠模型来研究脂质转运蛋白的功能。共同导师史蒂文·克林顿 (Steven Clinton) 和厄尔·哈里森 (Earl Harrison) 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，这使他们成为拟议的 K99 阶段和我的理想导师。过渡到植物化学营养遗传研究的职业生涯，我将每周在研究会议上与我的导师互动，但也会与咨询委员会互动， 该委员会将每半年举行一次会议，正式评估我的培训和研究进展，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，并将就 K99 研究的科学严谨性提供指导。环境：俄亥俄州立大学和韦克斯纳医学中心为俄亥俄州立大学的“作物到疾病预防”研究提供了令人惊讶的丰富环境。 “诊所”项目跨越三个学院，促进多层次、跨学科的研究项目，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。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，对饮食生物活性化合物营养遗传学、动力学和生物活性进行前沿研究，B) 培养饮食领域的未来领导者生物活性化合物和营养遗传学，以及 C) 促进对膳食植物化学物质的严格研究，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：植物化学物质和营养素：植物化学因素，我们将能够设计信息灵通的临床试验，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。该培训计划旨在让我成为一名训练有素的、跨学科的转化营养科学家，为我做好了独特的准备。迎接这一挑战。