PHYTOESTROGENS AND AGING: DOSE, TIMING & TISSUE

描述（由申请人提供）：本计划项目的总体研究目标是使用成熟的实验室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。虽然植物雌激素被美国老年人消费的有益效果，这些雌激素化合物的安全性还没有得到充分的评估，尽管这些化学品的消费量越来越高，特别是在老年妇女中。本计划项目的主题是，剂量，时间和暴露的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。由于需要对潜在风险和获益进行评价，因此出于伦理原因，这些研究不能在人体中进行，最好在适当的临床前实验室动物模型中进行。拟议的研究提供了一个系统的评估的作用，各种方案的植物雌激素暴露可能对靶器官是特别相关的老化，这些研究也将寻求确定植物雌激素对这些不同的靶组织的影响机制。 总之，P01的总体目标是使用完善的动物模型对植物雌激素饮食暴露的影响进行高度互动的研究，每种动物模型在研究乳腺癌进展为激素依赖性、肥胖和糖尿病风险以及认知功能方面具有特定优势。这一目标将通过四个互补的协同项目实现：（1）染料木黄酮和乳腺肿瘤的内分泌抵抗，（2）膳食植物雌激素和脂肪细胞发育，（3）膳食雌激素和衰老过程中的认知功能，以及（4）通过雌激素受体α和β的植物雌激素作用。研究人员将得到一个行政核心的帮助，该核心负责监督项目间会议，并提供预算，报告和外部咨询需求，一个分析和生物利用度核心，将为项目1-3提供血液和组织代谢水平的分析和标准化，以及一个饮食，基因组学和化学合成核心，将提供统一的饮食，通过微阵列和定量PCR方法进行基因表达谱分析，以及植物雌激素和植物雌激素代谢物的化学合成。

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.