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.

抽象的 末期肾脏疾病（ESRD）及其相关并发症的比例不成比例 与美国一般人口相比，退伍军人。目前约有45,500名退伍军人 血液透析。在美国，估计有500,000名ESRD患者接受维持血液透析 预计到2030年，这一数字将超过100万。在透析的退伍军人中 在透析当天，死亡的主要原因和死亡的风险特别高。长期 候选人的目标是进行研究，以改善透析的心血管结局 患者，是美国退伍军人健康的高度相关目标。研究：该建议将评估 透析驱动的危险因素导致心血管疾病的新型机制。透析相关 RBC磷酸盐代谢产物的改变导致心肌组织缺氧和远程低血压以及 了解这些变化的机制应导致改善新的治疗策略 该人群的心血管死亡率。特定的目标1将利用体外模型研究透析 影响2,3-DPG浓度的特定因素。 特定目标2将检查 透析过程中2,3-DPG和降压发作的变化。特定目标3将确定是否 透析过程中2,3-DPG的变化与心肌功能障碍有关，利用了新的定量 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发展成为一个独立和生产性的研究人员，研究了心血管并发症的 慢性肾脏疾病，专注于磷酸盐代谢，最终是慢性肾脏的其他方面 疾病时段骨病（CKD-MBD），这两个主题都与VA患者人群高度相关。博士 Sharma在此提案中的培训目标包括：1）在透析生理学方面发展专业知识 - 红细胞2,3-DPG的相关变化与心肌组织缺氧/缺血和诊断内的相关变化 低血压2）在解释方面发展专业知识，并进行多个多数处理 参数超声心动图图像3）在实验室技术方面获得了支持转化研究的技能 以及相关的高级生物统计方法。夏尔马博士将通过 由她的导师，课程工作和参加研讨会的研究。导师：Sharma博士有 在院士的指导中，组建了一个有成就的科学家团队，并具有良好的往绩记录 包括她的主要导师 - 金·莱恩·恩吉恩（Kim-Lien Nguyen）博士，她将退伍军人作为无创的 大洛杉矶弗吉尼亚州的心脏病专家/心脏成像专家，领导了一项富有成效的资金丰富的 心血管成像研究实验室的重点是开发，翻译和应用 高级心血管成像技术，包括超声心动图（超声）和磁性 谐振。 Sharma博士的联合主角是高级调查员，并在各自的领域闻名：博士。 Tomas Ganz（RBC生物学和铁），Isidro Salusky博士（矿物质代谢和CKD）以及Joachim IX博士 （弗吉尼亚州圣地亚哥的医师科学家心血管并发症和CKD）。他们将指导和协助 项目完成期间，数据分析，手稿准备和未来的制定 临床试验和赠款申请。 Sharma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，还获得动手 图像解释和相关实验室技术的培训。夏尔马博士得到了她的全部支持 机构及其职业发展将受益于与UCLA的持续合作伙伴关系，UCLA是世界知名的 具有广泛资源的研究大学。

项目成果

The Authors Reply.

• DOI: 10.1038/ki.2015.131
• 发表时间: 2015-07
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Dong Z

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