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: 10662216
• 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/10662216
• 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; Funding; Future; General Population; 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; Productivity; Prospective Studies; Records; Renal Replacement Therapy; Research; Research Personnel; Resources; Risk; Risk Factors; Scientist; Serum; Techniques; Temperature; Time; Tissues; Training; Translations; Universities; Veterans; Work; 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)及其相关并发症在 退伍军人与普通美国人相比。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名终末期肾病患者接受维持性血液透析 预计到2030年，这一数字将上升到100多万。在接受透析的退伍军人中，心血管疾病 是导致死亡的主要原因，在透析当天死亡风险尤其高。长期的 应聘者的目标是进行研究，以改善透析中的心血管结果 患者，这是一个与美国退伍军人健康高度相关的目标。研究：这项提案将对 透析驱动的危险因素导致心血管疾病的新机制。与透析相关的 红细胞磷酸代谢产物的改变导致心肌组织缺氧和透析中的低血压 了解这些变化的机制应该会导致新的治疗策略来改善 这一人群的心血管死亡率。特殊目标1将利用体外模型来研究透析 影响2，3-DPG浓度的特定因素。 具体目标2将考察两者之间的关系 透析过程中2，3-DPG和低血压发作的变化。具体目标3将决定是否 利用一种新的定量方法，透析期间2，3-DPG的变化与心肌功能障碍有关 基于实时超声心动图的成像方法。应聘者：该计划旨在帮助Dr。 夏尔马发展成为一名独立而富有成效的研究人员，研究 慢性肾脏疾病，重点是磷酸盐代谢，最终是慢性肾脏的其他方面 疾病-矿物性骨病(CKD-MBD)，这两个主题都与VA患者群体高度相关。Dr。 夏尔马在这项建议中的培训目标包括：1)发展透析生理学方面的专业知识- 红细胞2，3-DPG与心肌组织缺氧/缺血及透析内的相关变化 低血压2)培养解释方面的专业知识，并对多个项目进行高级处理 参数超声心动图3)掌握支持翻译研究的实验室技术，如 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 由她的导师指导的研究、课程作业和参加研讨会。导师：夏尔马博士有 组建了一支成就卓著的科学家团队，他们在院士的指导下取得了良好的成绩 包括她的主要导师阮金莲医生，他为退伍军人提供非侵入性服务 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 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)和磁力成像 共鸣。夏尔马博士的联合导师都是资深调查人员，在各自的领域都很有名气。 托马斯·甘茨(RBC生物学和铁)、伊西德罗·萨卢斯基博士(矿物质代谢和慢性肾脏病)和约阿希姆九世博士 (心血管并发症和CKD，弗吉尼亚州圣地亚哥内科科学家)。他们将指导和协助 申请者在项目完成期间，数据分析，稿件准备，以及未来的制定 临床试验和拨款申请。夏尔马博士将参加授课课程，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 图像解释和相关实验室技术培训。夏尔马博士得到了她的全力支持 她的职业发展将受益于与世界知名的加州大学洛杉矶分校的持续合作伙伴关系 拥有广泛资源的研究型大学。

项目成果

Elevated Fibroblast Growth Factor 23 Levels Are Associated With Greater Diastolic Dysfunction in ESRD.

成纤维细胞生长因子 23 水平升高与 ESRD 中更大的舒张功能障碍相关。

• DOI: 10.1016/j.ekir.2019.07.022
• 发表时间: 2019
• 期刊: Kidney international reports
• 影响因子: 6
• 作者: Sharma,Shilpa;Hanudel,MarkR;Ix,JoachimH;Salusky,IsidroB;Ganz,Tomas;Nguyen,Kim-Lien
• 通讯作者: Nguyen,Kim-Lien