Sex Differences in Renal Ammonia Metabolism

肾脏氨代谢的性别差异

• 批准号: 9894799
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894799
• 关键词: 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; Intestines; Investigation; K-Series Research Career Programs; Kidney; Laboratories; Lead; Maintenance; Male Castration; Manuscripts; Mediating; Medical center; Medicine; Mentors; Metabolic acidosis; Metabolism; Modeling; Mus; Musculoskeletal; Nephrology; Neurologic; Orchiectomy; Ovariectomy; Ovary; Performance; Phenotype; Physiological; Physiology; Ploidies; Postdoctoral Fellow; Prevalence; Process; Production; Progesterone; Proteins; Proximal Kidney Tubules; Publishing; Regulation; Research; Research Design; Research Personnel; Research Training; Resources; Role; Sex Chromosomes; Sex Differences; Statistical Methods; Stimulus; Structural Protein; 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; collecting tubule structure; 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.

项目概要 男性和女性在基本上所有生理系统中的基本生理学和病理生理学都不同。 这些生物学性别差异可能导致疾病患病率、进展率和治疗的差异 结果。了解这些差异可以有助于识别新的疾病机制和/或新的和 改善治疗机会。因此，非常需要对性领域进行更多研究 动物模型和人之间的差异。酸碱平衡对于维持酸碱平衡至关重要 肾的正常健康和氨代谢对维持酸碱平衡具有重要作用。我 已经表明基础氨排泄存在显着的性别差异，这是由于性别差异造成的 参与氨代谢和运输的多种重要蛋白质的表达。此外，我 研究表明，女性和男性肾脏之间存在显着的结构差异。因此， 该提案的总体目标是确定肾脏性别差异的根本机制 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。该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 使用性腺切除术和激素替代来调节肾氨代谢的激素 模型; 2) 确定性类固醇激素受体在性别依赖性差异发育中的作用 通过使用肾脏特异性 AR 和 ERα 缺失来影响氨代谢； 3）确定性别角色 使用四核心基因型模型研究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条件（例如代谢）的反应的影响 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。该职业发展奖将为哈里斯博士提供 需要额外的培训才能实现她成为独立调查员的目标，其中包括培训 在以下领域：1) 研究设计和实施，2) 各种研究的表现、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 多学科和多机构团队，5）资助和稿件撰写。哈里斯博士开发了一种 全面的计划，包括教学培训、实践和实验室经验以及强有力的指导 和顾问团队。佛罗里达大学医学院将提供学术和支持 具有完成研究和开发所需的设备、实验室空间和资源的环境 训练。在这项提案的最终成果中，哈里斯博士将准备获得作为研究员的独立性 随着肾脏病学和性别差异领域的持续研究。