Sex Differences in Renal Ammonia Metabolism

肾脏氨代谢的性别差异

• 批准号: 10886996
• 负责人: AUTUMN N HARRIS
• 金额: $ 15.85万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10886996
• 关键词: Acceleration; Acids; Advisory Committees; Affect; Ammonia; Androgen Receptor; Animal Model; Area; Cardiovascular system; Caring; Chromosome 3; Chromosomes; Chronic Kidney Failure; Collaborations; Cre-LoxP; Data; Development; Diagnostic tests; Disease; Disease model; Duct (organ) structure; Eating; Enzymes; Equipment; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Evaluation; Excretory function; Female; Florida; Four Core Genotypes; Functional disorder; Funding; Future; Generations; Goals; Gonadal Steroid Hormones; Grant; Health; Homeostasis; Hormones; Human; Immunologics; Institution; Intestines; Investigation; K-Series Research Career Programs; Kidney; Laboratories; Maintenance; Male Castration; Manuscripts; Mediating; Medical center; Medicine; Mentors; Metabolic acidosis; Metabolism; Modeling; Mus; Musculoskeletal; Nephrology; Neurologic; Orchiectomy; Ovariectomy; Ovary; Performance; Persons; Phenotype; Physiological; Physiology; Ploidies; Postdoctoral Fellow; Prevalence; Process; Production; Progesterone; Proteins; Proximal Kidney Tubules; Publishing; Regulation; Research; Research Design; Research Personnel; Resources; Role; Sex Chromosomes; Sex Differences; Statistical Methods; Stimulus; Structure; System; Techniques; Testing; Testis; Testosterone; Therapeutic; Training; Translating; Treatment outcome; United States National Institutes of Health; Universities; Writing; Y Chromosome; base; biological sex; body system; college; density; gonad development; human disease; improved; kidney cortex; laboratory experience; male; mortality; multidisciplinary; patient oriented; programs; protein expression; receptor; receptor expression; reproductive function; respiratory; response; sex; sexual dimorphism; sry Genes; steroid hormone receptor; supportive environment

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.

项目摘要 男性和女性在基本的生理学和病理生理学上基本上在所有的生理系统上都是不同的。 这些生物学上的性别差异会导致疾病患病率、进展率和治疗方法的差异 结果。理解这些差异可以用于识别新的疾病机制和/或新的和 改善治疗机会。因此，对性领域进行更多的研究是非常必要的 动物模型和人的差异。酸碱平衡对于维持 正常的健康和肾氨代谢在维持酸碱平衡中具有重要作用。我 已经表明，基础氨排泄量存在显著的性别差异，这是由以下方面的性别差异造成的： 参与氨代谢和运输的多种重要蛋白质的表达。而且我 已经表明女性和男性的肾脏在结构上有很大的不同。所以 本提案的总体目标是确定肾功能损害中这些性别差异的潜在机制。 氨代谢，并确定这些性别差异在生理相关疾病中的作用 模型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治疗中对肾氨代谢的调节作用 模型; 2）确定性类固醇激素受体在性别依赖性差异发展中的作用 通过使用肾特异性AR和ERα缺失在氨代谢中的作用; 3）确定性别的作用 使用四个核心基因型模型的染色体在肾氨代谢调节中的作用;以及，4） 确定性别对肾脏对氨代谢改变的反应的影响，如代谢性氨代谢， 酸中毒Autumn Harris，DVM，DACVIM（SAIM），是NIH T32资助的博士后研究员， 佛罗里达大学医学院。这个职业发展奖将为哈里斯博士提供 实现成为独立调查员的目标所需的额外培训，包括培训 在1）研究设计和实施，2）性能，解释和各种评估领域， 实验室技术和诊断测试，3）统计方法和解释，4）与 多学科和多机构的团队，5）赠款和手稿写作。哈里斯博士开发了一种 全面的课程，包括教学培训，实践和实验室经验，以及强大的指导 咨询团队。佛罗里达大学医学院将提供一个合议和支持 环境与设备，实验室空间，和完成研究所需的资源， 训练在这一建议的高潮，哈里斯博士将准备实现作为一个研究人员的独立性 随着肾脏学和性别差异领域的持续调查。