Microvascular Perfusion Assessment of Ischemic Diabetic Ulcers Using MRI

 应聘者：Gerd Brunner，医学硕士/博士，受过心血管成像和生物医学计算机科学方面的培训，是德克萨斯州休斯敦贝勒医学院动脉粥样硬化和血管医学部的第二年终身教职助理教授。这位候选人的职业目标是成为心血管成像领域的一名独立研究员。K25量化职业发展奖对于向独立过渡至关重要。该奖项将为研究提供额外的培训、指导和受保护的时间，以发展对动脉粥样硬化和糖尿病的原因、机制和临床方面的清楚了解，增强布伦纳博士的资质技能，并在进行临床成像研究方面获得先进的经验。K25奖项将为布伦纳博士提供必要的经验，以开发一个强大的独立心血管成像项目。布伦纳博士的初步研究、最近的出版物以及自第一次提交以来的新数据和多学科培训构成了这项申请的基础，并提供了他之前研究和培训的合乎逻辑的继续。德克萨斯医学中心是一个极好的环境，它为布伦纳博士提供了必要的设施和教育资源，以便他进入有针对性的指导阶段，以便发展成为一名独立的研究人员。指导团队和职业发展：Brunner博士和他的主要导师Christie Ballantyne MD是动脉粥样硬化、外周动脉疾病(PAD)和脂蛋白研究的国际公认领导者，他们组建了一支杰出的指导团队，其中包括创伤愈合和糖尿病溃疡的国际专家Lawrence Lavery，DPM，公共卫生硕士；临床心血管成像的国家专家Dipan Shah医学博士；糖尿病和心血管疾病的国际专家Ashok Balasubramanyam医学博士；磁共振成像(MRI)和MRI物理学的全国领先者Raja Muthupillai博士；心脏病、动脉粥样硬化和超声检查的国家专家Vijay Nambi医学博士/博士；以及乔尔·莫里塞特博士，他是血管成像和动脉粥样硬化领域的国际知名领导者。布伦纳博士的导师在研究和指导初级调查人员方面拥有丰富的经验，这从NIH资助的项目中可见一斑，其中包括为期+15年的机构T32培训补助金。他的指导团队和布伦纳博士已经就他职业发展的每一年的衡量标准达成了一致。根据过去的生产力，布伦纳博士将在头两年发表5篇手稿，第三年和第四年每年发表3-5篇文章，最后一年发表4-8篇。布伦纳博士将是他出版的作品中至少50%的第一作者。布伦纳博士的直接职业目标是获得一笔资金资助的职业发展奖。他的3年目标是完成教育和培训。他的4年目标是写一笔RO1的NIH拨款，以确保持续的资金。他6-7年的目标是晋升为终身教职的副教授，10年的目标是成为心血管成像领域的全国领先者和指导初级科学家。研究计划：糖尿病是一种多方面的疾病，与大血管(大血管疾病)并发症有关，如PAD和微血管并发症(小血管疾病)。高达40%的糖尿病缺血性溃疡在开放搭桥手术或血管内血运重建术后一年内不能愈合。这就提出了一个难题，即下肢缺血持续存在，否则看起来像是一条通畅的血管。一些研究表明，微循环的改变可能是导致缺血性糖尿病溃疡创面愈合不良的原因之一。然而，微循环与糖尿病合并缺血患者创面愈合的关系仍不清楚。在一开始识别不太可能实现伤口愈合的患者，可能会使患者和医疗保健系统受益。由于缺乏量化微血管循环的临床措施，这一领域受到严重阻碍。因此，这项建议将阐明骨骼肌微循环在糖尿病合并缺血性溃疡中所起的作用。Brunner博士此前已经证明了使用磁共振成像(MRI)方案评估健康对照组和PAD患者肌肉灌注(微血管循环)的可行性。申请人的最新数据显示，与健康对照组相比，PAD患者(包括糖尿病患者)的对比增强(CE)-MRI测量的骨骼肌灌注显著减少，这证实了其他组的结果。他的数据还显示，肌肉灌注在肌肉间显示出不同的模式，表明灌注异常，而CE-MRI骨骼肌灌注特征与估计的肾小球滤过率(EGFR)呈负相关，EGFR是微血管疾病的已知标志。这项建议将检验这样一种假设，即用CE-MRI在足部测量的微血管循环(骨骼肌灌注)与共病匹配的对照组相比，糖尿病缺血性溃疡患者的微血管循环受损，以及在临床指示的下肢血管重建术后1年，患有未愈合溃疡的糖尿病患者的基线微血管循环受损更严重。拟议的无创性MRI研究将首次提供糖尿病缺血性溃疡患者足部骨骼肌微循环的定量数据。这些研究将促进我们对微血管循环在糖尿病患者动脉血运重建术前后所起的作用的理解。

 DESCRIPTION (provided by applicant): The candidate, Gerd Brunner, MS/PhD is a quantitative researcher trained in cardiovascular imaging and biomedical computer science who is a second year tenure track Assistant Professor at the Division of Atherosclerosis and Vascular Medicine, Department of Medicine at Baylor College of Medicine, Houston, Texas. The candidate's career goal is to become an independent investigator in the field of cardiovascular imaging. The K25 Quantitative Career Development Award is of critical importance for transitioning to independence. The award will provide additional training, mentoring and protected time for research to develop a clear understanding of the causes, mechanisms, and clinical aspects of atherosclerosis and diabetes mellitus, enhance Dr. Brunner's grantsmanship skills, and to gain advanced experience in performing clinical imaging studies. The K25 award will provide Dr. Brunner with the necessary experience to develop a strong independent program in cardiovascular imaging. Dr. Brunner's preliminary studies, recent publications, and new data since the first submission and multidisciplinary training form the basis of this application and present a logical continuation of his previous research and training. The Texas Medical Center is a superb environment that provides the necessary facilities and educational resources for Dr. Brunner to pursue a targeted mentoring phase in order to develop into an independent investigator. Mentoring Team and Career Development: Dr. Brunner and his primary mentor Christie Ballantyne MD, an internationally recognized leader in atherosclerosis, peripheral arterial disease (PAD), and lipoprotein research, have assembled an outstanding mentoring team including Lawrence Lavery, DPM, MPH, an international expert in wound healing and diabetic ulcers; Dipan Shah, MD a national expert in clinical cardiovascular imaging; Ashok Balasubramanyam, MD an international expert in diabetes and cardiovascular disease; Raja Muthupillai, PhD a national leader in magnetic resonance imaging (MRI) and MRI physics; Vijay Nambi, MD/PhD a national expert in cardiology, atherosclerosis and ultrasonography; and Joel Morrisett, PhD an internationally known leader in vascular imaging and atherosclerosis. Dr. Brunner's mentors have tremendous experience in research and mentoring junior investigators, as evident by NIH funded projects including an institutional T32 training grant for +15 years. His mentoring team and Dr. Brunner have agreed on metrics for every year of his career development. Based on past productivity, Dr. Brunner will publish 5 manuscripts in the first 2 years, 3-5 articles annually in years 3 and 4, and 4-8 in the last year. Dr. Brunner will be the fist author on at least 50% of his published work. Dr. Brunner's immediate career goal is to obtain a funded career development award. His 3-year goal is to complete education and training. His 4-year goal is to write an RO1 NIH grant to secure continuous funding. His 6-7 year goal is to be promoted to Associate Professor with tenure and his 10-year goal is to be a national leader in cardiovascular imaging and to mentor junior scientists. Research Plan: Diabetes mellitus is a multi-facetted disease associated with macrovascular (large vessel disease) complications such as PAD and microvascular complications (small vessel disease). Up to 40% of ischemic diabetic ulcers do not heal after 1-year following either open bypass surgery or endovascular revascularization. This presents a conundrum, i.e., lower extremity ischemia persists in what otherwise appears to be a patent vessel. Several studies suggest that alterations in the microcirculation may contribute to the poor wound healing of ischemic diabetic ulcers. However, the association of microcirculation with wound healing in diabetics with ischemia remains unknown. Identifying patients who are unlikely to achieve wound healing at the outset, would likely benefit patients and the health care system. This field is severely hampered by the lack of clinical measures to quantify microvascular circulation. Therefore, this proposal will elucidate th role that skeletal foot muscle microcirculation plays in diabetics with ischemic ulcers. Dr. Brunner has previously demonstrated the feasibility of a magnetic resonance imaging (MRI) protocol to assess muscle perfusion (microvascular circulation) in healthy controls and PAD patients. The applicant's latest data show that skeletal muscle perfusion, as measured with contrast-enhanced (CE)-MRI is markedly reduced in PAD patients (including diabetics) compared to healthy controls, confirming results by other groups. His data also reveal that muscle perfusion shows heterogeneous patterns across muscle compartments indicating perfusion abnormalities, and CE-MRI skeletal muscle perfusion characteristics correlate inversely with estimated glomerular filtration rate (eGFR), a known marker of microvascular disease. This proposal will test the hypothesis that microvascular circulation (skeletal muscle perfusion), as measured with CE-MRI in the foot, is impaired in diabetics with ischemic ulcers compared to comorbidity matched controls and that baseline microvascular circulation is more impaired in diabetics with non-healing ulcers at 1 year after clinically indicated lower-extremity revascularization. The proposed non-invasive MRI studies will, for the first time, provide quantitative data on the skeletal foot muscle microcirculation in diabetics with ischemic ulcers. These studies will advance our understanding of the role that microvascular circulation plays in diabetics with ischemia before and after clinically indicated arterial revascularization.