Dietary Inorganic Phosphate as a Target for Nutritional intervention in Cancer

描述（由申请人提供）： 越来越明显的是，饮食可以对功能基因组学产生深远的影响。然而，这一领域的研究才刚刚开始被用于治疗。了解个体饮食成分在促进健康或疾病方面的作用将为干预疾病预防和治疗提供新的机会。众所周知，前列腺癌受生活方式因素如饮食的影响。我们的初步体外研究结果表明，前列腺细胞所暴露的无机磷酸盐的浓度是细胞生长潜力的重要诱发因素，并改变了转化和转移相关基因，如骨桥蛋白和Egr-1的表达。无机磷酸盐也是细胞能量的重要组成部分，这引发了许多关于与过量和/或有限的细胞磷酸盐相关的事件的问题：可用的血清磷酸盐的量是否会改变细胞在体内的生长特性？在转化压力的存在下，可利用的磷酸盐的量是否会改变细胞的反应？令人惊讶的是，很少有人知道改变血清无机磷酸盐水平对与健康和疾病相关的细胞和组织行为的潜在积极或消极影响。随着美国饮食中磷酸盐的含量继续上升，超过FDA已经认为的高水平，了解与这种常见饮食元素相关的长期健康益处和风险将非常重要。该应用程序将测试以下假设：减少无机磷酸盐饮食可以减少前列腺癌的发生和/或进展。为了验证这一假设，我们将利用现有的和明确定义的小鼠模型，转基因小鼠前列腺腺癌（TRAMP）。具体地，来自本申请的结果将确定相对于高磷酸盐饮食，低无机磷酸盐饮食是否减少TRAMP模型中前列腺癌的发展和/或进展。将通过泌尿生殖道重量和分级组织学测量癌症发展和进展的程度。根据初步结果，血清无机磷水平的改变可能通过两种可能的机制影响前列腺功能; 1）通过改变特定基因如骨桥蛋白和Egr-1的表达直接影响细胞功能，我们将通过免疫组织化学和肿瘤的分子表征来测量，和/或2）改变一种或多种循环因子的水平，例如我们将在血清中测量的维生素D或骨桥蛋白。

DESCRIPTION (provided by applicant): It is becoming increasingly apparent that diet can have profound effects on functional genomics. However, this area of research has only begun to be exploited for therapeutic benefit. Understanding the role of individual dietary components in promoting health or disease will open new opportunities to intervene in both disease prevention and treatment. Cancer of the prostate is known to be influenced by life style factors such as diet. Our preliminary in vitro results suggest that the concentration of inorganic phosphate that prostate cells are exposed to is an important predisposing factor in the growth potential of cells and alters the expression of transformation and metastasis associated genes such as osteopontin and Egr-1. Inorganic phosphate is also a critical component of cellular energy which raises a number of questions regarding the events associated with excess and/or limited cellular phosphate: Does the amount of available serum phosphate alter the growth properties of the cell in vivo? Does the amount of available phosphate alter the response of the cell in the presence of a transformational pressure? Surprisingly, little is known about the potential positive or negative effects of altered serum levels of inorganic phosphate on cell and tissue behavior related to health and disease. As the amount of phosphate in the American diet continues to rise beyond levels already considered high by the FDA it will be important to understand the long-term health benefits and risks associated with this common dietary element. This application will test the hypothesis that: a reduced inorganic phosphate diet reduces development and/or progression of prostate cancer. To test this hypothesis we will utilize an existing and well defined mouse model, the transgenic adenocarcinoma of the mouse prostate (TRAMP). Specifically, results from this application will determine whether a diet low in inorganic phosphate reduces development and/or progression of prostate cancer in the TRAMP model, relative to a diet high in phosphate. The extent of cancer development and progression will be measured by genitourinary tract weight and graded histology. Based on preliminary results, altered levels of serum inorganic phosphate might influence prostate function by two possible mechanisms; 1) directly affecting cell function by altering the expression of specific genes such as osteopontin and Egr-1, which we will measure by immunohistochemistry and molecular characterization of the neoplasia and/or 2) altering the levels of one or more circulating factors such as vitamin D or osteopontin which we will measure in the serum.