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.

摘要 终末期肾病（ESRD）及其相关并发症的发生率在以下人群中不成比例地高： 退伍军人相比，一般美国。S.人口目前约有45，500名退伍军人获得 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年这一数字将超过100万。在接受透析、心血管疾病的退伍军人中 是死亡的主要原因，在透析当天死亡的风险特别高。长期 候选人的目标是进行研究，将导致改善心血管透析的结果 这是一个与美国退伍军人健康高度相关的目标。研究：该提案将评估 透析驱动的风险因素导致心血管疾病的新机制。透析相关 RBC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导致新的治疗策略， 心血管疾病死亡率。具体目标1将利用体外模型研究透析 影响2，3-DPG浓度的特定因素。 具体目标2将研究 透析期间2，3-DPG和水肿发作的变化。具体目标3将确定是否 透析期间2，3-DPG的变化与心肌功能障碍有关，利用一种新的定量方法， 基于真实的时间超声心动图的成像方法学。候选人：该计划旨在帮助博士。 夏尔马发展成为一个独立的和富有成效的研究人员调查心血管并发症的 慢性肾脏疾病，重点关注磷酸盐代谢，最终关注慢性肾脏疾病的其他方面 疾病-矿物质骨疾病（CKD-MBD），这两个主题与VA患者人群高度相关。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- 红细胞2，3-DPG的相关变化与心肌组织缺氧/缺血和透析中 低血压2）发展专业知识的解释，和先进的处理多- 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。Sharma博士将通过以下方式完成这些活动 她的导师，课程，并参加研讨会监督的研究。导师：Sharma博士 组建了一个有成就的科学家团队，他们在院士的指导下有着良好的记录 包括她的主要导师-Kim-Lien Nguyen博士，他作为一个非侵入性的退伍军人 大洛杉矶VA的心脏病学家/心脏成像专家，并领导了一个富有成效的，资金充足的 心血管成像研究实验室专注于开发，翻译和应用 先进的心血管成像技术，包括超声心动图（超声）和磁共振成像技术。 共振Sharma博士的共同导师都是资深研究人员，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 San Diego的医师科学家）。他们将指导和协助 申请人在完成项目，数据分析，手稿准备，并制定未来 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，并获得实践经验， 图像判读和相关实验室技术培训。夏尔马医生得到了她的全力支持 机构，她的职业发展将受益于与加州大学洛杉矶分校，一个世界知名的 拥有广泛资源的研究型大学。