Sex Differences in Renal Ammonia Metabolism

项目摘要 男性和女性的基本生理学和病理生理学基本上在所有的生理系统中都不同。 这些生理性别差异可能会导致疾病患病率、进展率和治疗方法的差异 结果。了解这些差异有助于识别新的疾病机制和/或新的和 改善了治疗机会。因此，非常需要对性领域进行更多的研究。 动物模型和人的差异。酸碱动态平衡对维持 正常的健康和肾脏氨代谢在维持酸碱平衡方面起着重要作用。我 已经表明在基础氨排泄方面存在显著的性别差异，这是由于 参与氨代谢和转运的多种重要蛋白质的表达。此外，我 已经表明，女性和男性的肾脏在结构上存在显著差异。因此， 这项建议的总体目标是确定这些肾脏性别差异的潜在机制。 并确定这些性别差异在生理性相关疾病中的作用 模特们。这一目标将通过以下具体目标进行评估：1)确定性类固醇的作用 激素在性腺切除和激素替代中调节肾氨代谢的作用 模型；2)确定性类固醇激素受体在性别依赖差异形成中的作用 在氨代谢中使用肾脏特异性AR和ERα缺失；3)确定性别的作用 用四核心基因模型研究染色体在调节肾脏氨代谢中的作用 确定性别对肾脏对氨代谢改变条件的反应的影响 酸中毒。秋季·哈里斯，DACVIM(SAIM)DVM，NIH T32资助的博士后研究员 佛罗里达大学医学院。这一职业发展奖将为哈里斯博士提供 为实现她成为独立调查员的目标需要额外的培训，其中包括培训 在以下领域：1)研究设计和实施；2)执行、解释和评估 实验室技术和诊断测试，3)统计方法和解释，4)与 多学科、多机构团队；5)助学金和稿件写作。哈里斯博士已经研制出一种 全面的计划，包括教学培训、实践和实验室经验，以及强大的指导 和顾问团队。佛罗里达大学医学院将提供合议性和支持性 具有完成研究和研究所需的设备、实验室空间和资源的环境 训练。在这一提议达到顶峰时，哈里斯博士将准备好作为一名研究人员实现独立 随着肾脏病领域和性别差异的不断研究。

Project Summary Males and females differ in their basic physiology and pathophysiology in essentially all physiological systems. These biological sex differences can lead to differences in disease prevalence, progression rates and treatment outcomes. Understanding these differences can serve to identify new disease mechanisms and/or new and improved therapeutic opportunities. Thus, there is an immense need for additional research into the area of sex differences in both animal models and people. Acid-base homeostasis is of critical importance for maintaining normal health and renal ammonia metabolism has a major role in the maintenance of acid-base homeostasis. I have shown there are significant sex differences in basal ammonia excretion that result from sex differences in the expression of multiple important proteins involved in ammonia metabolism and transport. Furthermore, I have shown that there are significant structural differences between the female and male kidney. Hence, the overall objective of this proposal is to determine the underlying mechanisms of these sex differences in renal ammonia metabolism and to determine the role of these sex differences in physiological relevant disease models. This objective will be evaluated via the following specific aims: 1) determine the role of sex steroid hormones in the regulation of renal ammonia metabolism using a gonadectomy and hormone replacement model; 2) determine the role of sex steroid hormone receptors in the development of sex-dependent differences in ammonia metabolism through the use of kidney-specific AR and ERα deletion; 3) determine the role of sex chromosomes in the regulation of renal ammonia metabolism using the four core genotype model; and, 4) determine the effect of sex on the renal response to conditions of altered ammonia metabolism such as metabolic acidosis. Autumn Harris, DVM, DACVIM (SAIM), is an NIH T32-funded post-doctoral research fellow at the University of Florida College of Medicine. This career development award will provide Dr. Harris with the additional training needed to achieve her goal of becoming an independent investigator, which includes training in the areas of 1) study design and implementation, 2) performance, interpretation, and evaluation of various laboratory techniques and diagnostic tests, 3) statistical methods and interpretation, 4) collaboration with a multidisciplinary and multi-institutional team, 5) grant and manuscript writing. Dr. Harris has developed a comprehensive program including didactic training, practical and laboratory experience, and a strong mentoring and advisory team. The University of Florida College of Medicine will provide a collegial and supportive environment with the equipment, laboratory space, and resources necessary to complete the research and training. At the culmination of this proposal, Dr. Harris will be poised to achieve independence as a researcher with continuing investigation in the field of nephrology and sex differences.