Quantitative Assessment of Cardiac Disease in Duchenne Muscular Dystrophy

杜氏肌营养不良症心脏病的定量评估

• 批准号: 8754724
• 负责人: Jonathan Harvey Soslow
• 金额: $ 15.24万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-21 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8754724
• 关键词: Academic Medical Centers; Adrenal Cortex Hormones; Affect; Award; Binding; Biological Markers; Biomedical Engineering; Blood; Cardiac; Cardiology; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Caring; Cause of Death; Cessation of life; Childhood; Cicatrix; Clinic; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Complex; Data; Development; Development Plans; Diagnosis; Disease; Disease Progression; Distant; Duchenne muscular dystrophy; Dystrophin; Echocardiography; Endocrine; Environment; Evaluation; Exercise; Faculty; Fibrosis; Fostering; Functional disorder; Funding; Future; Gene Mutation; Glycoproteins; Goals; Heart; Heart Diseases; Heart failure; Image; Incidence; Inflammation; Insulin-Like Growth Factor I; Investigation; Isometric Exercise; Knowledge; Lead; Left Ventricular Dysfunction; Left Ventricular Ejection Fraction; Limb structure; Link; Location; Magnetic Resonance Imaging; Maintenance; Maps; Master of Science; Measures; Medical; Mentors; Mentorship; Methods; Modeling; Modification; Monitor; Morbidity - disease rate; Muscle; Muscle function; Muscular Dystrophies; Myocardial; Myocardium; Neuregulin 1; Neuregulins; Organ; Pathway interactions; Patient Care Team; Patients; Peptides; Phenotype; Physics; Physiology; Play; Population; Prior Therapy; Process; Property; Proteins; Qualifying; Quality of life; Randomized Controlled Trials; Recording of previous events; Research; Research Design; Research Infrastructure; Research Personnel; Residual state; Respiratory Failure; Risk; Role; Serum; Signal Pathway; Signal Transduction; Skeletal Muscle; Specialist; Staging; Structure; Supportive care; Surrogate Markers; Techniques; Testing; Therapeutic; Therapeutic Agents; Therapy Clinical Trials; Therapy Evaluation; Time; Training; Transesophageal Echocardiography; Universities; Wheelchairs; advanced disease; boys; career; career development; clinical care; design; expectation; experience; extracellular; imaging modality; improved; innovation; insight; mortality; muscle form; neuregulin-4; non-invasive imaging; novel; novel therapeutics; patient oriented research; patient population; premature; prevent; professor; programs; public health relevance; research study; screening; skeletal; skills

DESCRIPTION (provided by applicant): This Mentored Patient-Oriented Research Career Development proposal will provide for a structured environment with expert mentorship and an adequate subject population facilitating Dr. Jonathan Soslow's development as an independent clinical investigator. Dr. Soslow is an Assistant Professor of Pediatric Cardiology at Vanderbilt University Medical Center. He trained in pediatric cardiology at Vanderbilt University, including a fourth year in advanced cardiac imaging (complex transthoracic echocardiography, transesophageal echocardiography, and cardiac MRI). Dr. Soslow's long-term goal is to use non-invasive methods to improve diagnosis and monitoring in DMD cardiomyopathy and other forms of pediatric cardiomyopathy. This K23 proposal will strengthen his knowledge of physics and physiology, allowing him to better interface with bioengineers and physicists in the design and implementation of new MRI sequences. He will gain a unique skillset in advanced pediatric cardiac imaging, biomarker evaluation, and statistical analysis that will facilitate his transitionto an independent investigator. Dr. Soslow's mentorship team is uniquely qualified to support him in this endeavor. Strengths include expertise in non-invasive imaging and physiology (Damon), specialist in DMD cardiac care and research and general clinical research design and study conduct (Markham), expertise in heart failure and biomarkers (Sawyer), and expertise in cardiac MRI (Raman and Arai). His mentors have a documented history of successful mentorship of junior faculty. The skills that Dr. Soslow will develop during this award, combined with his current didactic coursework in the Master of Science in Clinical Investigation (MSCI) program, his excellent mentorship, and the research environment at Vanderbilt, will set him on the path towards a career as an independent investigator with R01 funding. Duchenne muscular dystrophy (DMD) is a devastating disease that affects 1 in 3500 boys. Despite significant research advances, patients with DMD continue to die, wheelchair bound, in their twenties. Cardiovascular disease is the leading cause of death in DMD, but the timing and pace of progression to cardiomyopathy is variable. While echocardiographic screening can detect cardiac dysfunction, echocardiography is a poor surrogate marker of disease. Echocardiographic dysfunction likely represents an end stage fibrotic myocardium that is unresponsive to remodeling therapies. Studies demonstrate that early initiation of cardiac specific therapy, prior to manifest systolic dysfunction, can decrease morbidity and delay mortality. Therefore, a better surrogate marker would allow for earlier, focused therapy, potentially altering disease progression and reducing cardiovascular mortality. Fibrosis plays an integral role in the development of DMD cardiomyopathy. Serum and imaging biomarkers of fibrosis are promising methods to identify patients at risk for an accelerated pace of progression to heart failure. Research has demonstrated that proteins secreted by skeletal muscle tissue, or myokines, can modulate the function of distant organs. This concept led us to hypothesize that maintenance of skeletal muscle mass and function, through the secretion of said myokines, is cardioprotective. Our preliminary data fit this model. We have demonstrated a direct relationship between preserved skeletal and cardiac function after loss of ambulation and have established that DMD patients with heart failure have lower levels of neuregulin- 1B (NRG), a candidate myokine. The central hypothesis of this proposal is that serum and imaging biomarkers detect subclinical myocardial fibrosis and can be used as surrogate markers of disease in DMD. We further postulate that maintaining residual skeletal muscle function is cardioprotective, and that this cardioprotection is modulated by NRG and insulin-like growth factor I (IGF-I). Aim 1 will evaluate serum and imaging biomarkers of fibrosis and assess whether abnormalities in these biomarkers precede left ventricular dysfunction. This aim will have a direct, meaningful application to clinical care in DMD, allowing for early cardiovascular therapy, assessment and modification of this therapy, and evaluation of novel therapeutic agents. Aim 2 will evaluate the interaction between skeletal and cardiac muscle function. The results of this aim will inform future studies to prevent DMD cardiomyopathy, including a study evaluating continued corticosteroid therapy after loss of ambulation and a study on the effects of isometric exercise on cardiomyopathy. Aim 3 will assess the postulated cell-signaling mechanism of skeletal and cardiac interaction by evaluating two candidate myokines, NRG and IGF-I. This aim will potentially lead to future therapeutic strategies in DMD. This project will advance our understanding of DMD cardiomyopathy and the interaction between skeletal and cardiac muscle, allowing for meaningful changes in DMD care and spring-boarding the candidate to a successful career as an independent investigator.

描述（由申请人提供）：这项以患者为导向的研究职业发展提案将提供一个有专家指导的结构化环境和足够的受试者群体，以促进乔纳森·索斯洛博士作为独立临床研究者的发展。索斯洛博士是范德比尔特大学医学中心儿科心脏病学助理教授。他在范德比尔特大学接受了儿科心脏病学培训，其中包括 第四年学习高级心脏成像（复杂经胸超声心动图、经食管超声心动图和心脏 MRI）。 Soslow 博士的长期目标是使用非侵入性方法来改善 DMD 心肌病和其他形式的小儿心肌病的诊断和监测。这项 K23 提案将加强他的物理学和生理学知识，使他能够在设计和实施新的 MRI 序列时更好地与生物工程师和物理学家沟通。他将获得高级儿科心脏成像、生物标志物评估和统计分析方面的独特技能，这将有助于他过渡为独立研究者。索斯洛博士的导师团队非常有资格支持他的这一努力。优势包括非侵入性成像和生理学方面的专业知识 (Damon)、DMD 心脏护理和研究以及一般临床研究设计和研究实施方面的专家 (Markham)、心力衰竭和生物标志物方面的专业知识 (Sawyer) 以及心脏 MRI 方面的专业知识 (拉曼)和新井）。他的导师有着成功指导初级教师的历史记录。 Soslow 博士在获奖期间将培养的技能，结合他目前在临床研究理学硕士 (MSCI) 项目中的教学课程、他出色的指导以及范德堡大学的研究环境，将使他走上成为一名医学博士的道路。获得 R01 资助，担任独立调查员。杜氏肌营养不良症 (DMD) 是一种毁灭性的疾病，每 3500 名男孩中就有 1 人受到影响。尽管研究取得了重大进展，但 DMD 患者仍然在二十多岁的时候死于轮椅上。心血管疾病是 DMD 死亡的主要原因，但进展为心肌病的时间和速度是可变的。虽然超声心动图筛查可以检测心脏功能障碍，但超声心动图是疾病的不良替代标志。超声心动图功能障碍可能代表对重塑治疗无反应的终末期纤维化心肌。研究表明，在出现收缩功能障碍之前尽早开始心脏特异性治疗可以降低发病率并延迟死亡率。因此，更好的替代标志物将允许更早、有针对性的治疗，有可能改变疾病进展并降低心血管死亡率。纤维化在 DMD 心肌病的发展中起着不可或缺的作用。纤维化的血清和成像生物标志物是识别有加速发展为心力衰竭风险的患者的有前途的方法。研究表明，骨骼肌组织分泌的蛋白质或肌因子可以调节远端器官的功能。这个概念使我们推测，通过分泌所述肌因子来维持骨骼肌质量和功能具有心脏保护作用。我们的初步数据适合这个模型。我们已经证明了失去行走能力后保留的骨骼和心脏功能之间存在直接关系，并确定患有心力衰竭的 DMD 患者的神经调节蛋白-1B (NRG)（一种候选肌因子）水平较低。该提案的中心假设是血清和成像生物标志物可检测亚临床心肌纤维化，并可用作 DMD 疾病的替代标志物。我们进一步假设维持残余骨骼肌功能具有心脏保护作用，并且这种心脏保护作用是由 NRG 和胰岛素样生长因子 I (IGF-I) 调节的。目标 1 将评估纤维化的血清和影像生物标志物，并评估这些生物标志物的异常是否先于左心室功能障碍。这一目标将对 DMD 的临床护理产生直接、有意义的应用，允许早期心血管治疗、对该疗法的评估和修改以及新型治疗药物的评估。目标 2 将评估骨骼肌和心肌功能之间的相互作用。这一目标的结果将为未来预防 DMD 心肌病的研究提供信息，包括一项评估失去行走能力后继续皮质类固醇治疗的研究以及一项关于等长运动对心肌病影响的研究。目标 3 将通过评估两种候选肌因子 NRG 和 IGF-I 来评估假定的骨骼和心脏相互作用的细胞信号传导机制。这一目标可能会导致 DMD 的未来治疗策略。该项目将增进我们对 DMD 心肌病以及骨骼和心肌之间相互作用的理解，从而使 DMD 护理发生有意义的变化，并帮助候选人作为独立研究者获得成功的职业生涯。