In vivo Studies of Creatine Kinase Kinetics by 31P Magnetization Transfer MRS

通过 31P 磁化转移 MRS 进行肌酸激酶动力学的体内研究

• 批准号: 8517116
• 负责人: Adil Bashir
• 金额: $ 12.24万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517116
• 关键词: Adenosine Triphosphate; Animal Experiments; Animal Model; Animals; Anterior; Basic Science; Biochemical; Biological Models; Breathing; Cardiac; Cardiovascular Diseases; Caring; Cause of Death; Chemicals; Chest; Chest wall structure; Clinical Research; Complications of Diabetes Mellitus; Conflict (Psychology); Coupled; Creatine Kinase; Creatine Kinase MB Isoenzyme; Data; Detection; Development; Diabetes Mellitus; Diagnosis; Disease; Echocardiography; Energy Metabolism; Ensure; Enzymes; Evaluation; Functional disorder; Gold; Heart; Heart failure; Human; Individual; Isoenzymes; Kinetics; Knowledge; Lead; Left Ventricular Dysfunction; Life; MM form creatine kinase; Magnetic Resonance Spectroscopy; Measurement; Measures; Medical; Metabolic; Metabolism; Methodology; Methods; Modeling; Monitor; Motion; Muscle; Myocardial; Myocardial Infarction; Myocardium; Obesity; Patients; Phosphocreatine; Phosphorus; Preparation; Prevention; Production; RF coil; Rattus; Reaction; Relative (related person); Research Project Grants; Signal Transduction; Skeletal Muscle; Streptozocin; Surface; System; Techniques; Testing; Time; Tissues; Work; diabetic; diabetic cardiomyopathy; diabetic rat; heart function; improved; in vivo; indexing; inorganic phosphate; magnetic field; novel strategies; public health relevance; research study; respiratory; technique development; tool

DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of death in the U.S. despite improvements in prevention, detection, and treatment. Although the cause of heart failure is multi-factorial, there is increasing evidence that a mismatch in myocardial energy supply and demand contributes to the development of left ventricular dysfunction. Heart uses chemical energy in the form of adenosine triphosphate (ATP) to support systolic and diastolic function. The creatine kinase (CK) system acts as the primary ATP reserve for the heart and instantaneously supplies ATP for its contractile function. Changes in the CK system are seen in heart failure in both the human and animal myocardium indicative of impaired delivery of ATP to energy consuming systems. Therefore it is logical to hypothesize that the development of new noninvasive quantitative methods for serial studies of energy metabolism would be especially valuable for enhancing our understanding of the development and progression of heart failure. Magnetization transfer phosphorous-31 magnetic resonance spectroscopy (MRS) is an ideal tool to measure the kinetics of high energy phosphate metabolism in living tissue, and has been used for such in isolated heart preparations and open chest animal experiments. Methods for in vivo CK flux measurements in hearts have been lagging because of the sensitivity and complexity of the technique. The major problems arise from long examination time and signal contamination from the skeletal muscles in chest wall, which is further exacerbated by respiratory motion. A new approach to measure in vivo CK flux, overcoming the issues of lengthy examination time will be developed. Coupled with novel approach to eliminate signal contamination from the chest muscles using inhomogeneous magnetic field gradient surface spoiling will lead to clinically useful MRS technique to quantify myocardial CK flux in vivo and, thus provide accurate evaluation of energy metabolite turnover in the heart. The initial technique development will focus on small animal experiments and the results will be compared to open chest experiments to evaluate the accuracy of the technique. In vivo sensitivity of the technique will be established using a diabetic rat heart model where CK flux is expected to vary over a large range. Correlations will be obtained with the biochemical measurements of CK isoenzyme. The research project will conclude with the development and feasibility testing of the technique for clinical research. PUBLIC HEALTH RELEVANCE (provided by applicant): Obesity, diabetes and related complications especially cardiovascular disease are a huge burden on individuals in particular and US economy in general. Development of new and improved techniques to understand in vivo metabolism and generate new knowledge will be of paramount importance to understand, diagnose, treat and manage these complications. The proposed project aims to develop new methodology to measure and understand energy disorders in cardiovascular disease and the techniques developed will be critically useful to advance basic research and medical care.

描述（由申请人提供）：尽管在预防、检测和治疗方面有所改进，但心血管疾病仍是美国的主要死亡原因。虽然心力衰竭的原因是多因素的，但越来越多的证据表明，心肌能量供应和需求的不匹配有助于左心室功能障碍的发展。心脏以三磷酸腺苷（ATP）的形式使用化学能来支持收缩和舒张功能。肌酸激酶（CK）系统作为心脏的主要ATP储备，并立即为其收缩功能提供ATP。CK系统的变化见于人类和动物心肌的心力衰竭，表明ATP向能量消耗系统的递送受损。因此，这是合乎逻辑的假设，新的非侵入性定量方法的系列研究的能量代谢的发展将是特别有价值的，以提高我们的理解的发展和进展的心力衰竭。 磁化转移磷-31磁共振波谱（MRS）是一种理想的工具， 测量活组织中高能磷酸盐代谢的动力学，并已被用于此类 在离体心脏制备和开胸动物实验中。用于体内CK通量的方法 心脏的测量由于该技术的敏感性和复杂性而一直滞后。 主要问题是检查时间长和骨骼信号污染 胸壁的肌肉，这是进一步加剧呼吸运动。一种新的测量方法 在体内CK流量，克服了检查时间过长的问题，将开发。加上 一种新的方法来消除信号污染的胸肌使用不均匀 磁场梯度表面破坏将导致临床上有用的MRS技术来量化 体内心肌CK通量，从而提供准确的能量代谢物周转的评价， 心 最初的技术开发将集中在小动物实验上，结果将是 与开胸实验进行比较，以评估该技术的准确性。体内灵敏度 技术将使用糖尿病大鼠心脏模型建立，其中CK通量预计在 大范围用CK同工酶的生化测定值进行相关性分析。的 研究项目将以临床应用技术的开发和可行性测试结束。 research. 公共卫生相关性（由申请人提供）：肥胖、糖尿病和相关并发症，特别是心血管疾病，是个人和美国经济的巨大负担。开发新的和改进的技术来了解体内代谢和产生新的知识将是至关重要的理解，诊断，治疗和管理这些并发症。拟议的项目旨在开发新的方法来测量和了解心血管疾病中的能量障碍，所开发的技术将对推进基础研究和医疗保健至关重要。