PHYTOESTROGENS AND AGING: DOSE, TIMING & TISSUE

描述（由申请人提供）：本项目的总体研究目标是利用成熟的实验动物模型，评估膳食植物雌激素对乳腺癌进展、脂肪组织和大脑的潜在有益或有害影响。尽管美国老年人食用植物雌激素具有公认的有益作用，但这些雌激素化合物的安全性尚未得到充分评估，尽管这些化学物质的高水平消费量不断增加，特别是在老年妇女中。本项目的主题是暴露的剂量、时间和持续时间都将是植物雌激素暴露在不同靶组织中的生物学结果的决定因素。由于潜在的风险和益处都需要评估，由于伦理原因，这些研究不能在人体中进行，最好是在适当的临床前实验动物模型中进行。这些研究提供了一个系统的评估，不同方案的植物雌激素暴露可能对与衰老特别相关的靶器官的作用，这些研究也将寻求确定植物雌激素对这些不同靶组织的作用机制。

DESCRIPTION (provided by applicant): The overall research objective of this Program Project is to evaluate the potential beneficial or detrimental effects of dietary phytoestrogens on breast cancer progression, adipose tissue and the brain, using well-established laboratory animal models. Although phytoestrogens are consumed by older Americans for their perceived beneficial effects, these estrogenic compounds have not been adequately evaluated for safety, despite increasing consumption of these chemicals at high levels, especially among older women. The theme of this Program Project is that dosage, timing, and duration of exposure will all be determinants of the biological outcome of phytoestrogen exposure in different target tissues. Since both potential risks and benefits need to be evaluated, these studies cannot be conducted in humans for ethical reasons and can best be conducted in appropriate pre-clinical laboratory animal models. The proposed studies provide a systematic evaluation of the role that various regimens of phytoestrogen exposure may have on target organs that are of special relevance in aging, and these studies will also seek to determine the mechanism of phytoestrogen effects on these different target tissues. In summary, the overall goal of the P01 is to conduct highly interactive investigations of the effects of phytoestrogen dietary exposure using well established animal models, each having specific advantages for the study of: breast cancer progression to hormone independence, obesity and risk of diabetes, and cognitive function. This goal will be achieved through four complementary, synergistic projects: (1) Genistein and Endocrine Resistance in Breast Tumors, (2) Dietary Phytoestrogens and Adipocyte Development, (3) Dietary Estrogens and Cognitive Function During Aging, and (4) Phytoestrogen Action Through Estrogen Receptors alpha and beta. Investigators will be aided by an Administrative Core that oversees inter-project meetings and provides budgetary, reporting and external advisory needs, an Analytical and Bioavailability Core that will provide analysis and standardization of blood and tissue isoflavone levels for projects 1-3, and a Dietary, Genomics and Chemistry Synthesis Core that will provide uniform diets, gene expression profiling analysis by microarray and quantitative PCR methods, and chemical synthesis of phytoestrogens and phytoestrogen metabolites.