Phosphorus Absorption and Balance in Normal Physiology and Chronic Kidney Disease

 描述（由申请方提供）：由于肾功能进行性丧失导致的血清磷（P）升高和P稳态相关异常是慢性肾病（CKD）患者心血管功能障碍和死亡率的主要驱动力。此外，血清P升高与健康人群的死亡率增加有关。肠道磷吸收是磷代谢的一个重要组成部分，但研究不足。阐明影响和调节P吸收的因素对于制定控制CKD患者和一般人群中P代谢异常及其相关后果的策略至关重要。主要研究者（PI）的长期职业目标是 开发一个独立的临床和转化研究计划，重点是确定影响和调节健康和CKD人群肠道磷吸收的因素。为实现这一目标，PI将在健康受试者和CKD患者中开展一系列临床研究，并在CKD动物模型中进行补充实验。这完全符合NIDDK的使命，即通过支持肾脏疾病和内分泌及代谢疾病的研究和研究培训来改善健康和生活质量。本项目的具体目标是：1）确定与健康成人相比，早期CKD患者的肠道P吸收效率，当膳食P被限制时，P吸收如何受到影响，以及确定有机和无机膳食来源的P生物利用度; 2）在使用进行性CKD-MBD的Cy/+大鼠模型的机制研究中确定P吸收效率和膳食P摄入对P吸收的响应，确定肠道磷转运蛋白NaPi-2b的定位对磷吸收的作用; 3）确定正常儿童的全身磷平衡，以及膳食钙摄入量、人口统计学和生化因素对CKD儿童磷平衡的影响，从而为将来的研究奠定基础。一个具有与本项目相关的互补专业知识的导师团队将监督PI在磷吸收和代谢方面的研究培训，以及在导师奖励期间的职业发展指导。PI将参与骨和矿物质代谢、慢性肾脏疾病、临床研究和负责任的研究行为方面的教育经验。普渡大学和印第安纳州大学医学院沿着印第安纳州临床研究中心为矿物质代谢的临床和基础研究提供了良好的研究和智力资源环境。

 DESCRIPTION (provided by applicant): Elevated serum phosphorus (P) and related abnormalities in P homeostasis due to progressive loss of kidney function are primary driving forces behind cardiovascular dysfunction and mortality in chronic kidney disease (CKD) patients. In addition, elevated serum P is associated with increased mortality in the healthy general population. Intestinal P absorption is a critical, yet understudied component in P metabolism. Elucidating factors that influence and regulate P absorption is essential for developing strategies to control abnormal P metabolism and associated consequences in CKD patients, and in the general population. The principle investigator (PI)'s long-term career goal is to develop an independent clinical and translational research program focused on determining the factors that influence and regulate intestinal P absorption in healthy and CKD populations. To achieve this, the PI will conduct a series of clinical studies in healthy subjects and patients with CKD, supported by complementary experiments in animal models of CKD. This fits well within the mission of the NIDDK to improve health and quality of life through support of research and research training in kidney disease and endocrine and metabolic diseases. The goals of the specific aims of this project are: 1) to determine intestinal P absorption efficiency in patients wth early stages of CKD in comparison to healthy adults, how P absorption is affected when dietary P is restricted, and to determine P bioavailability from organic and inorganic dietary sources; 2) to determine P absorption efficiency and response to dietary P intake on P absorption in a mechanistic study using the Cy/+ rat model of progressive CKD-MBD, and determine the role of localization of the intestinal P transporter NaPi-2b on P absorption; and 3) to determine total-body P balance in normal children and the effects of dietary Ca intake, demographic, and biochemical factors on P balance leading to future studies in children with CKD. A team of mentors with complementary expertise relevant to this project will oversee the PI's research training in P absorption and metabolism, as well as career development guidance during the mentored award period. The PI will partake in educational experiences in bone and mineral metabolism, chronic kidney disease, clinical research, and responsible conduct of research. Purdue University and Indiana University School of Medicine, along with the Indiana Clinical Research Center, provide excellent environments in terms of research and intellectual resources for clinical and basic studies in mineral metabolism.