Physiology of Male Reproductive Hormones in Aging

衰老过程中男性生殖激素的生理学

• 批准号: 6550729
• 负责人: CHRISTOPHER R FOX
• 金额: $ 5.21万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6550729
• 关键词: Leydig cells; age difference; aging; clinical research; gonadotropin releasing factor; hormone regulation /control mechanism; human subject; hypothalamic pituitary axis; injection /infusion; ketoconazole; luteinizing hormone; male; physiology; pituitary gland; pituitary gonadal axis; postdoctoral investigator; secretion; testosterone

Testosterone concentrations decline by 1-2% annually as men age, and free testosterone concentrations decline even more rapidly (3-4% per year). Lower serum testosterone concentrations have been associated with important health consequences, including reduced bone mineral density, increased risk of hip fracture, loss of muscle mass, decreased libido and fertility, and increased cardiovascular disease. HYPOTHESIS I will test whether glucocorticoids mediate down- regulation of urea transporter proteins by altering transcription. Specific Aim 1 will test whether glucocorticoids down-regulate UT-A and/or UT-B protein or mRNA expression. Specific Aim 2 will determine the element mediating glucocorticoid-induced suppression of urea transporter promoter activity. HYPOTHESIS II will test whether chronic lithium administration down-regulates urea transporter protein(s) by increasing glucocorticoids. Specific Aim 3 will test whether adrenalectomy prevents long-term down-regulation of urea transporter protein(s) in lithium-treated rats. Specific Aim 4 will test whether elevated lithium levels perturb urea transporter phosphorylation or function in rat inner medulla or in EcR-293 cells that have been stably transfected with a specific urea transporter isoform. HYPOTHESIS III will test whether urea transporter proteins are down- regulated during aldosterone-escape. Specific Aim 5 will test whether mineralocorticoids down-regulate UT-A and/or UT-B protein or mRNA expression.

随着男性年龄的增长，睾酮浓度每年下降1-2%，游离睾酮浓度下降得更快（每年3-4%）。 较低的血清睾酮浓度与重要的健康后果有关，包括骨矿物质密度降低，髋部骨折风险增加，肌肉质量损失，性欲和生育能力下降，以及心血管疾病增加。假设我将测试糖皮质激素是否通过改变转录介导尿素转运蛋白的下调.特异性目的1将测试糖皮质激素是否下调UT-A和/或UT-B蛋白或mRNA表达。特异性目的2将确定介导糖皮质激素诱导的尿素转运蛋白启动子活性抑制的元件。假设II将测试长期锂给药是否通过增加糖皮质激素下调尿素转运蛋白。具体目标3将测试肾上腺切除术是否防止锂处理大鼠中尿素转运蛋白的长期下调。 具体目标4将测试升高的锂水平是否干扰尿素转运蛋白磷酸化或在大鼠内髓质或已用特定尿素转运蛋白亚型稳定转染的EcR-293细胞中的功能。假设III将测试在醛固酮逃逸过程中尿素转运蛋白是否下调。 具体目标5将测试盐皮质激素是否下调UT-A和/或UT-B蛋白或mRNA表达。