Physiology of Male Reproductive Hormones in Aging

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%）。血清睾酮浓度降低与重要的健康后果有关，包括骨密度降低、髋部骨折风险增加、肌肉量减少、性欲和生育能力下降以及心血管疾病增加。假设1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Aim 1将检测糖皮质激素是否下调UT-A和/或UT-B蛋白或mRNA表达。特异性Aim 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。假设二将检验长期给锂是否通过增加糖皮质激素来下调尿素转运蛋白。特异性目的3将测试肾上腺切除术是否会阻止锂处理大鼠尿素转运蛋白的长期下调。特异性Aim 4将测试锂水平升高是否会干扰大鼠髓内或稳定转染特定尿素转运蛋白异构体的EcR-293细胞中的尿素转运蛋白磷酸化或功能。假设III将检验尿素转运蛋白在醛固酮逃逸过程中是否下调。特异性Aim 5将检测矿化皮质激素是否下调UT-A和/或UT-B蛋白或mRNA表达。

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.