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Grant Abstract: Mechanisms of Carotenoid Transport and Interactions with Nutrient Absorption

Grant Number: 5K99AT008576-03
PI Name: Moran
Project Title: Mechanisms of Carotenoid Transport and Interactions with Nutrient Absorption

Abstract: 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, ?arotene (pro-vitamin A) and ?ocopherol (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 r

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