Dynamic Changes in Erythrocyte 2,3 DPG as a Driver of Cardiac Dysfunction in End Stage Kidney Disease

红细胞 2,3 DPG 的动态变化是终末期肾病心脏功能障碍的驱动因素

• 批准号: 10426221
• 负责人: Shilpa Sharma
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10426221
• 关键词: Acute; Address; Affect; Affinity; American; Applications Grants; Area; Award; Biological Markers; Biometry; Blood; Bone Diseases; Brain Hypoxia-Ischemia; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell membrane; Cellular biology; Cessation of life; Chronic Kidney Failure; Clinical; Clinical Trials; Critical Illness; Data; Data Analyses; Development; Dialysis patients; Dialysis procedure; Disease Progression; Echocardiography; Educational workshop; End stage renal failure; Erythrocytes; Event; Excess Mortality; Formulation; Foundations; Funding; Future; Goals; Healthcare; Heart; Hemodialysis; Hemoglobin; Hypotension; Hypotensives; Hypoxia; Image; Image Analysis; Imaging Techniques; In Vitro; Institution; Iron; Kidney; Kidney Diseases; Laboratories; Laboratory Research; Lead; Link; Los Angeles; Magnetic Resonance; Maintenance; Manuscripts; Measures; Mentors; Mentorship; Metabolism; Methodology; Minerals; Morbidity - disease rate; Myocardial; Myocardial Ischemia; Myocardial dysfunction; Myocardial tissue; Observational Study; Outcome; Outpatients; Oxygen; Pathogenesis; Patients; Phosphorus; Physicians; Physiology; Play; Population; Preparation; Prevalence; Prospective Studies; Records; Renal Replacement Therapy; Research; Research Personnel; Research Proposals; Resources; Risk; Risk Factors; Scientist; Serum; Supervision; Techniques; Temperature; Time; Tissues; Training; Translations; Universities; Veterans; Work; base; cardiovascular collapse; cardiovascular imaging; career; career development; clinical investigation; design; diphosphoglycerate; experimental study; extracellular; health goals; heart imaging; hemodynamics; high risk; high risk population; improved; improved outcome; in vitro Model; inorganic phosphate; mortality; mortality risk; novel; novel therapeutic intervention; patient population; programs; quantitative imaging; skills; translational study; treatment strategy; ultrasound

ABSTRACT End-stage renal disease (ESRD) and its associated complications are disproportionately higher in veterans compared to the general U. S. population. Approximately 45,500 veterans currently receive hemodialysis. In the U.S., there is an estimated 500,000 ESRD patients receiving maintenance hemodialysis and this number is predicted to rise to over 1 million by 2030. In veterans on dialysis, cardiovascular disease is the leading cause of death and the risk of death is particularly high on the day of dialysis. The long-term goal of the candidate is to conduct research that will lead to improved cardiovascular outcomes in dialysis patients, a highly relevant goal for the health of American veterans. Research: This proposal will evaluate novel mechanisms by which dialysis-driven risk factors contribute to cardiovascular disease. Dialysis-related alterations in RBC phosphate metabolites lead to myocardial tissue hypoxia and intra-dialytic hypotension and understanding the mechanisms of these changes should lead to new therapeutic strategies for ameliorating cardiovascular mortality in this population. Specific Aim 1 will utilize an in vitro model to investigate dialysis specific factors affecting 2,3-DPG concentrations. Specific Aim 2 will examine the relationship between changes in 2,3-DPG and hypotensive episodes during dialysis sessions. Specific Aim 3 will determine whether changes in 2,3-DPG during dialysis are associated with myocardial dysfunction, utilizing a novel quantitative imaging methodology based on real time echocardiography. Candidate: The program is designed to help Dr. Sharma develop into an independent and productive researcher investigating cardiovascular complications of chronic kidney disease, focusing on phosphate metabolism and eventually other aspects of chronic kidney disease-mineral bone disorder (CKD-MBD), both topics highly relevant to the VA patient population. Dr. Sharma's training objectives in this proposal include to: 1) develop expertise in the physiology of dialysis- related alterations in erythrocyte 2,3-DPG associated with myocardial tissue hypoxia/ischemia and intra-dialytic hypotension 2) develop expertise in interpretation, and advanced processing of multi- parametric echocardiographic images 3) gain skills in laboratory techniques supporting translational studies as well as related advanced bio-statistical approaches. Dr. Sharma will accomplish these activities through studies supervised by her mentors, coursework, and participation in workshops. Mentors: Dr. Sharma has assembled a team of accomplished scientists with proven track records in the mentorship of academicians including her primary mentor- Dr. Kim-Lien Nguyen, who serves veterans as a non-invasive cardiologist/cardiac imaging expert at the Greater Los Angeles VA and leads a productive, well-funded cardiovascular imaging research laboratory focused on the development, translation, and application of advanced cardiovascular imaging techniques, including echocardiography (ultrasound) and magnetic resonance. Dr. Sharma's co-mentors are senior investigators and renowned in their respective fields: Dr. Tomas Ganz (RBC biology and iron), Dr. Isidro Salusky (mineral metabolism and CKD), and Dr. Joachim Ix (cardiovascular complications and CKD, Physician Scientist at VA San Diego). They will instruct and assist the applicant during completion of the project, data analysis, manuscript preparation, and formulation of future clinical trials and grant applications. Dr. Sharma will take didactic courses to obtain further training in quantitative biomarker analyses, pertinent aspects of quantitative echocardiography and also obtain hands-on training in image interpretation and relevant laboratory techniques. Dr. Sharma has the full support of her institution, and her career development will benefit from ongoing partnerships with UCLA, a world-renowned research university with a wide range of resources.

抽象的 终末期肾病 (ESRD) 及其相关并发症在 退伍军人与美国普通民众的比较。目前约有 45,500 名退伍军人接受 血液透析。在美国，估计有 500,000 名 ESRD 患者接受维持性血液透析 预计到 2030 年，这一数字将增至超过 100 万。在接受透析的退伍军人中，心血管疾病 是死亡的主要原因，透析当天的死亡风险特别高。长期来看 候选人的目标是进行能够改善透析心血管结局的研究 患者，这是与美国退伍军人的健康高度相关的目标。研究：该提案将评估 透析驱动的危险因素导致心血管疾病的新机制。透析相关 红细胞磷酸盐代谢物的改变导致心肌组织缺氧和透析中低血压 了解这些变化的机制应该会带来新的治疗策略来改善 该人群的心血管死亡率。具体目标 1 将利用体外模型来研究透析 影响 2,3-DPG 浓度的具体因素。 具体目标 2 将检查之间的关系 透析过程中 2,3-DPG 的变化和低血压发作。具体目标 3 将决定是否 透析过程中 2,3-DPG 的变化与心肌功能障碍相关，利用一种新的定量方法 基于实时超声心动图的成像方法。候选人：该计划旨在帮助博士。 Sharma 发展成为一名独立且富有成效的研究人员，研究心血管并发症 慢性肾脏病，重点关注磷酸盐代谢以及慢性肾脏病的其他方面 疾病-矿物质性骨病 (CKD-MBD)，这两个主题都与 VA 患者群体高度相关。博士。 Sharma 在本提案中的培训目标包括：1) 发展透析生理学方面的专业知识- 与心肌组织缺氧/缺血和透析中相关的红细胞 2,3-DPG 的相关变化 低血压 2) 发展解释和高级处理多方面的专业知识 参数超声心动图图像 3) 获得支持转化研究的实验室技术技能 以及相关的先进生物统计方法。夏尔马博士将通过以下方式完成这些活动 由她的导师指导的学习、课程作业和参加研讨会。导师：Sharma 博士 组建了一支由有成就的科学家组成的团队，他们在院士的指导下拥有良好的记录 其中包括她的主要导师 Kim-Lien Nguyen 博士，他以非侵入性的方式为退伍军人提供服务 大洛杉矶退伍军人管理局的心脏病专家/心脏成像专家，领导着一个富有成效、资金充足的团队 心血管影像研究实验室专注于心血管影像的开发、转化和应用 先进的心血管成像技术，包括超声心动图（超声波）和磁力图 谐振。 Sharma 博士的共同导师都是高级研究人员，在各自领域享有盛誉： Tomas Ganz（红细胞生物学和铁）、Isidro Salusky 博士（矿物质代谢和 CKD）和 Joachim Ix 博士 （心血管并发症和 CKD，VA 圣地亚哥医师科学家）。他们将指导和协助 申请人在项目完成、数据分析、稿件准备和未来制定期间 临床试验和拨款申请。夏尔马博士将参加教学课程以获得进一步的培训 定量生物标志物分析、定量超声心动图的相关方面，并获得实践机会 图像解释和相关实验室技术的培训。 Sharma博士得到了她的全力支持 她的职业发展将受益于与加州大学洛杉矶分校（UCLA）的持续合作关系，加州大学洛杉矶分校是世界著名的大学 拥有广泛资源的研究型大学。