Phospholipid Signaling in Fish oil-induced Growth Inhibi

20多年来，流行病学研究已经报道了膳食脂肪对以下风险的影响： 前列腺癌实验数据表明，n-3多不饱和脂肪酸（PUFA）抑制，而n-6 PUFA刺激前列腺癌细胞生长。然而，PUFA的作用机制尚不清楚。 n-3和n-6 PUFA是必需脂肪酸，是生存所必需的。哺乳动物不能合成这些 脂肪酸从头开始，既不能将n-6转化为n-3，也不能将n-3转化为n-6。因此，它们必须从饮食中摄取。 鱼油是n-3多不饱和脂肪酸的丰富来源。我们假设n-3 PUFA结合到 磷脂的sn-2位和富含n-3 PUFA的磷酸肌醇影响Akt信号传导 前列腺细胞生长抑制的基因表达。在这个项目中，我们将研究 富含n-3脂肪酸饮食对前列腺癌进展的抑制作用及其作用机制。 我们的具体目标是：确定n-3脂肪酸对前列腺癌增殖、进展的影响， 和转移。我们将评估n-3饮食对前列腺癌增殖，组织学进展， 生物标志物（基因、蛋白质和脂质）的表达、生存和转移;确定是否时机 n-3脂肪酸摄入量的差异影响前列腺癌。我们将决定早期和/或晚期摄入 将对前列腺癌产生类似于终生摄入n-3脂肪酸的效果。临床上 重要的是要知道儿童是否摄入n-3脂肪酸以及是否补充n-3脂肪酸 在前列腺癌的发展是有益的;确定n-3脂肪酸的影响， 磷酸肌醇的定位和Akt信号通路。我们将确定n-3脂肪酸 PIPs影响Pdk和Akt蛋白的定位、激活和下游信号传导。 我们利用我们在体内和体外、小鼠和人类模型系统方面的优势。第一 随着时间的推移，与前列腺中鱼油饮食相关的分子变化（mRNA和脂质）将被 进行了全面系统的分析。此外，传统的路径剥离方法将 也可用于研究鱼油对前列腺癌的作用机制。

For more than 2 decades, epidemiologic studies have been reported on the effect of dietary fat on the risk of prostate cancer. Experimental data indicate that n-3 polyunsaturated fatty acids (PUFAs) inhibit whereas n-6 PUFAs stimulate prostate cancer cell growth. However, the mechanism of PUFA's effect is unknown. n-3 and n-6 PUFAs are essential fatty acids and necessary for survival. Mammals cannot synthesize these fatty acids cte novo, neither can convert n-6 to n-3 or vice versa. Therefore they have to be taken in from diet. Fish oil is a rich source of n-3 polyunsaturated fatty acids. We hypothesize that n-3 PUFAs incorporate into the sn-2 position of phospholipids, and the n-3 PUFA-enriched phosphoinositides affect the Akt signaling pathway, regulate expression of genes resulting in prostate cell growth inhibition. In this project, we will study the suppression of prostate cancer progression by n-3 fatty acid enriched diet and its mechanism of action. Our specific aims are: Determine the effect of n-3 fatty acids on prostate cancer proliferation, progression and metastasis. We will assess the n-3 diet on prostate cancer proliferation, histological progression, expression of biomarkers (genes, proteins and lipids), survival and metastasis; Determine whether the timing of n-3 fatty acid intake differentially affects prostate cancer. We will determine whether early- and/or lateintake will have a similar effect on prostate cancer to life-long intake of n-3 fatty acids. Clinically, it is important to know whether childhood intake of n-3 fatty acids and whether n-3 fatty acids supplementation after the development of prostate cancer are beneficial; Determine the effect of n-3 fatty acids on the localization of phosphoinositides and on the Akt signaling pathway. We will determine whether n-3 fatty acid containing PIPs affect Pdk and Akt protein localization, activation and downstream signaling. We take advantage of our strengths of in vivo and in vitro, mouse and human model systems. For the first time, molecular changes (mRNA and lipid) associated with fish oil diet in the prostate will be comprehensively and systematically analyzed. In addition, conventional pathway dissection approach will also be applied to study the mechanism of action of fish oil on prostate cancer.