COX2-Regulated Testosterone Biosynthesis in Male Aging

COX2 调节男性衰老中的睾酮生物合成

• 批准号: 6964703
• 负责人: XINGJIA WANG
• 金额: $ 22.28万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6964703
• 关键词: Leydig cells; aging; arachidonate; enzyme mechanism; gel mobility shift assay; gene deletion mutation; gene expression; genetic regulation; genetically modified animals; hormone regulation /control mechanism; laboratory mouse; lipoxygenase; luteinizing hormone; male; nucleic acid sequence; phosphoproteins; prostaglandin endoperoxide synthase; steroid hormone biosynthesis; testosterone; tissue /cell culture

DESCRIPTION (provided by applicant): It is well known that blood testosterone concentration decreases in male aging resulting in a decline in physiological functions. The rate-limiting step of testosterone biosynthesis is transfer of the substrate cholesterol to the mitochondrial inner membrane to begin the steroidogenic process. Steroidogenic acute regulatory (StAR) protein is critical for this cholesterol transfer. However, StAR protein has been shown to be significantly reduced in the aged Leydig cell and results in a decrease in mitochondrial cholesterol transfer. Recent studies suggested that cyclooxygenase-2 (COX2) produces a tonic inhibition of StAR gene expression. We have shown that COX2 increases in the aged Leydig cells and the increase in COX2 is associated with the decreases in StAR protein and blood testosterone. Intriguingly, the decreases in blood testosterone were reversed by feeding the aged rats a COX2 inhibitor. These studies suggest that a novel and previously uncharacterized mechanism is involved in testosterone decline during male aging. To study the molecular mechanism for the role of COX2 in testosterone biosynthesis in the course of aging and to evaluate approaches to reverse or delay the age-related decline in testosterone biosynthesis, the following Aims are proposed: 1) over expressing the COX2 gene in Leydig cells to study the effect of COX2 expression on StAR gene expression and steroid hormone production; 2) to study the effects of the COX2 knock-out on luteinizing hormone-stimulated StAR gene expression and testosterone production in mice; 3) to study the role of 5-lipoxygenase in the regulatory effect of COX2 on StAR gene expression and testosterone production in Leydig cells; 4) to identify the arachidonic acid metabolites produced in the COX2 pathway that inhibit StAR gene expression and testosterone production; 5) to determine the elements in StAR promoter DNA sequences responsive to the identified metabolites. The long-term objectives of this project are to understand the molecular mechanism for the role of COX2 in testosterone biosynthesis in the aging process and to explore the potential for new drug development or application of COX2 inhibitors to improve the health of the aged male.

描述（由申请人提供）：众所周知，男性衰老的血液睾丸激素浓度降低，导致生理功能下降。睾丸激素生物合成的速率限制步骤是将底物胆固醇转移到线粒体内膜以开始类固醇生成过程。类固醇生成急性调节（Star）蛋白对于这种胆固醇转移至关重要。然而，已显示恒星蛋白在老年leydig细胞中显着降低，并导致线粒体胆固醇转移的降低。最近的研究表明，环氧酶-2（COX2）产生了对星基因表达的补品抑制作用。我们已经表明，老年leydig细胞的COX2增加，COX2的增加与恒星蛋白和血液睾丸激素的降低有关。有趣的是，血液睾丸激素的降低是通过喂养老年大鼠Cox2抑制剂来逆转的。这些研究表明，在男性衰老期间，一种新颖且以前未表征的机制参与睾丸激素的下降。 To study the molecular mechanism for the role of COX2 in testosterone biosynthesis in the course of aging and to evaluate approaches to reverse or delay the age-related decline in testosterone biosynthesis, the following Aims are proposed: 1) over expressing the COX2 gene in Leydig cells to study the effect of COX2 expression on StAR gene expression and steroid hormone production; 2）研究COX2敲除对小鼠激素刺激的恒星基因表达和睾丸激素产生的影响； 3）研究5-脂氧酶在leydig细胞中Cox2对恒星基因表达和睾丸激素产生的调节作用中的作用； 4）确定在COX2途径中产生的蛛网膜酸代谢产物，该途径抑制了恒星基因表达和睾丸激素的产生； 5）确定响应于鉴定的代谢物的恒星启动子DNA序列中的元素。该项目的长期目标是了解COX2在睾丸激素生物合成中的作用的分子机制，并探索新药开发或应用COX2抑制剂来改善老年男性健康的潜力。