Mitochondrial-based Determinants of Sex Differences in Acute Kidney Injury

急性肾损伤性别差异的线粒体决定因素

• 批准号: 10274740
• 负责人: LISA M CURTIS
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10274740
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Age; Animal Model; Atherosclerosis; Bilateral; Bioenergetics; Biology; Body Temperature; Caring; Characteristics; Chronic Kidney Failure; Cisplatin; Clinical; Clinical Research; Cost of Illness; Critical Illness; Data; Estrogen Receptors; Estrogens; Excision; Female; Fingerprint; Foundations; Future; Gender; Generations; Gonadal Hormones; Gonadal Steroid Hormones; Gonadal structure; Hormones; Housing; Incidence; Individual; Injury; Injury to Kidney; Institution; Intervention; Investigation; Kidney; Knowledge; Lead; Long-Term Effects; Low Prevalence; Menopause; Mitochondria; Mitochondrial DNA; Modeling; Mouse Strains; Mus; Nuclear; Organelles; Outcome; Pathologic; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmacology; Physiology; Pre-Clinical Model; Predisposition; Proteomics; Renal function; Reperfusion Injury; Resistance; Rodent; Role; Sex Differences; Signal Transduction; Temperature; Testing; Testosterone; Therapeutic; Woman; acute liver injury; base; body system; cis-female; clinical care; effective intervention; fatty acid metabolism; inflammatory milieu; male; men; mitochondrial dysfunction; mouse model; new therapeutic target; novel; pre-clinical; preclinical study; preservation; response to injury; sex; transcriptome sequencing; transgender; transgender men; transgender women

Acute kidney injury (AKI) afflicts substantial numbers of hospitalized patients, particularly those who are critically ill. Because protection from AKI in females is observed both clinically and in animal models, a better elucidation of the underlying biology of this protection may be essential to providing novel, effective intervention to both females and males with AKI. In support of a sex-based susceptibility to AKI, we have shown that female mice undergoing cisplatin-induced AKI (CP) have preserved renal function compared to males, which have significantly worse AKI. Clarity in the mechanisms that underpin resistance of females to renal injury has the potential to illuminate unique pathological mechanisms and represents a critical gap in our knowledge. Mitochondrial dysfunction is noted consistently as a contributor to the outcomes of AKI, and estrogen alters mitochondrial bioenergetics, perhaps via estrogen receptors that may be present in mitochondria. The primacy of mitochondrial function in sex-defined susceptibility will be confirmed in this proposal by examining a novel mouse model, developed at our institution, of mitochondrial-nuclear exchange (MNX) (Aim 1). These mice have an exchange between two strains of mice such that the MNX mice have nuclear characteristics of one strain of mice and the mitochondrial characteristics of another strain of mice. Our preliminary data demonstrate that the parental strains of the MNX mice have different sex-based profiles in susceptibility to AKI allowing for the investigation of the influence of these organelles in an injury model. A second modulation of mitochondrial function will be examined with thermoneutrality, the ambient temperature at which no additional mitochondrial shunting to heat generation is required to maintain core body temperature. Standard vivarium temperatures are typically at ~22-23C (TS), while thermoneutral temperatures for rodents is ~30C (TT). Thermoneutrality alters sex-differences in other organ systems, but has not been studied in AKI and will be examined in these studies (Aim 2). Examination of changes in mitochondrial function with administration of estrogen or testosterone to modulate susceptibility to AKI have not investigated long-term hormone administration. Long-term administration of hormones, particularly cross-sex administration reflecting the status of transgender individuals, has been minimally studied, and not at all in the kidney (Aim 3). The integrated overall hypothesis is that mitochondrial bioenergetics and dynamics alters susceptibility to AKI in a sex-specific manner. In establishing how sex differences are modulated in these different paradigms, these studies will provide the baseline understanding needed to better define “female AKI” and determine nuanced differences that may be exploited in interventions.

急性肾损伤（阿基）困扰着大量住院患者，特别是那些危重患者。 伊利诺伊州由于在临床和动物模型中均观察到对女性阿基的保护作用，因此更好地阐明 这种保护的潜在生物学可能是必要的，以提供新的，有效的干预， 阿基的女性和男性。为了支持基于性别的阿基易感性，我们已经证明雌性小鼠 与男性相比，接受顺铂诱导的阿基（CP）的患者保留了肾功能， 严重的阿基。明确了女性对肾损伤的抵抗机制， 潜在的阐明独特的病理机制，并代表了我们的知识的关键差距。 线粒体功能障碍一直被认为是阿基结局的一个因素，雌激素改变了AKI的预后。 线粒体生物能量学，可能通过雌激素受体，可能存在于线粒体。至上 线粒体功能的性别定义的易感性将被证实在这个建议，通过检查一个新的 小鼠模型，在我们的机构开发的髓核交换（MNX）（目的1）。这些小鼠具有 两种小鼠品系之间的交换，使得MNX小鼠具有一种小鼠品系的细胞核特征， 小鼠和另一种小鼠的线粒体特征。我们的初步数据表明， MNX小鼠的亲本品系在对阿基的易感性方面具有不同的基于性别的特征， 研究这些细胞器在损伤模型中的影响。线粒体的第二种调节 功能将用热中性进行检查，在该环境温度下，没有额外的线粒体 需要分流到热量产生以维持核心体温。标准的动物园温度是 通常为~22-23 ℃（TS），而啮齿动物的热中性温度为~30 ℃（TT）。热中性改变 其他器官系统中的性别差异，但尚未在阿基中进行研究，并将在这些研究中进行检查 (Aim 2）。雌激素或睾酮对线粒体功能的影响 调节对阿基的易感性尚未研究长期激素施用。长期行政管理 激素，特别是反映变性人地位的跨性别给药， 研究最少，在肾脏中根本没有研究（目标3）。综合的总体假设是， 生物能量学和动力学以性别特异性方式改变对阿基的易感性。在确定性如何 差异在这些不同的范例中得到调制，这些研究将提供基线理解 需要更好地定义“女性阿基”，并确定在干预措施中可能利用的细微差别。