Microvascular Perfusion Assessment of Ischemic Diabetic Ulcers Using MRI



 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.