The Interplay between Glucose Metabolism and Heat in Kidney Disease using a Metabolomics Approach

项目总结 Roxana Chias博士，RN是第一代双语拉丁裔，她的目标是成为一名独立的NIH- 受资助的护士科学家在以下领域制定可持续研究计划 葡萄糖代谢和 肾脏疾病。K23奖项的支持将提供专门的研究时间，从而实现 基础培训和指导，以加深她对以下问题的理解：1) 葡萄糖代谢 途径和热暴露与血管紧张素转换酶 代谢组学研究在农民肾脏疾病中的应用 方法；以及2)设计和管理社区参与的干预试验，以降低 脆弱人群中的热应激、肾功能障碍和血糖失调。中暑是主要原因 在美国，与天气有关的死亡人数中，农场工人是一个特别脆弱的职业部门 与中暑相关的疾病(HRI)。美国农业部门有200-300万工人面临中暑风险 相关死亡率比一般劳动力人口的死亡率高35倍。在最后一次 十年来的大量研究表明，高温暴露与患急性肾脏疾病的风险之间存在联系。 伤害(AKI)。AKI在农场工人中潜伏和不明原因的上升的慢性影响，以及 不成比例的HRI负荷和重复的热应激诱导的脱水还没有被很好地理解。这个 易患糖尿病等健康状况在AKI风险中可能起的作用尚未得到证实 检查过了。虽然研究已经记录了与高温相关的危险因素和身体对 高温，很少有研究考虑到葡萄糖代谢和高环境热条件 是急性肾损伤的危险因素，但对体内潜在的代谢途径知之甚少。 对热应激的反应。这个项目的目标是描述农场工人的生理表型。 使用非靶向、高分辨率代谢组学(HRM)，跨越季节和暴露(室内与室外) 比较代谢特征，并检查HRI临床特征(包括CORE)之间的关联 体温、心率、脱水、HRI症状)；炎症生物标志物(IL-10、IL-6、IL-8、IL-1β、 肿瘤坏死因子-α、热休克蛋白72、热休克蛋白90)；肾脏生物标志物(血清肌酐、尿素氮、表皮生长因子受体、蛋白尿、尿酸； 和血糖临床特征(糖化血红蛋白、AM空腹血糖和PM血糖水平)。 这项拟议的研究将探索糖代谢和HRI的相互作用，并增进我们对 AKI的生理基础和肾功能。新陈代谢组谱的整合将增加 通过指出潜在的新陈代谢机制和结果来说明科学的状态 对热应激的生理反应。

PROJECT SUMMARY Roxana Chicas, PhD, RN is a 1st generation bilingual Latina and her goal is to become an independent NIH- funded nurse scientist developing a sustainable research program in the area of glucose metabolism and kidney disease. Support from the K23 award will provide the dedicated research time that will enable fundamental training and mentorship to further her understanding of: 1) the relationship of glucose metabolic pathways and heat exposure and the development of kidney disease in farmworkers using a metabolomics approach; and 2) the design and management of community-engaged intervention trials to decrease the risk of heat stress, renal dysfunction, and glucose dysregulation in vulnerable populations. Heat is the leading cause of weather-related deaths in the US, and farmworkers comprise an occupational sector particularly vulnerable to heat-related illness (HRI). Between 2-3 million workers in the US agricultural industry are at risk of heat related mortality at a rate that is 35 times greater than that of the general workforce population. In the last decade a number of investigations have shown a link between heat exposure and the risk of acute kidney injury (AKI). The chronic effects of the insidious and unexplained uptick of AKI among farmworkers, and the disproportionate burden of HRI and repetitive heat stress-induced dehydration are not well understood. The role that predisposing health conditions such as prediabetes may play in the risk of AKI has not been examined. While studies have documented heat-related risk factors and the body’s physiologic response to heat, few investigations have considered whether glucose metabolism and high environmental heat conditions are a risk factor for acute kidney injury, and less is known about the metabolic pathways underlying the body’s response to heat stress. The goal of this project is to characterize the physiologic phenotypes of farmworkers across seasons and exposures (indoors v. outdoors), using non-targeted, high-resolution metabolomics (HRM) to compare metabolomic profiles, and examine the associations between HRI clinical profiles (including core body temperature, heart rate, dehydration, HRI symptoms); inflammation biomarkers (IL-10, IL-6, IL-8, IL-1β, TNF-α, HSP72, HSP90); renal biomarkers (serum creatinine, BUN, eGFR, proteinuria, uric acid; aldosterone, and copeptin); and glucose clinical profiles (HbA1c, AM fasting blood glucose, and PM blood glucose levels). This proposed study will explore interplay of glucose metabolism and HRI and advance our understanding of the physiologic underpinnings of AKI and renal function. The incorporation of metabolomic profiles will add to the state of the science by indicating the underlying metabolic mechanisms and consequences of the physiologic response to heat stress.