This revised proposal describes a five year training program and experimental approach for the development of the applicant towards becoming an independent clinician scientist. This application was previously reviewed favorably (impact score 31, pay line 30) and requested adjustments have been made complying with reviewer critiques. Also, since the first submission, the applicant has published two first author manuscripts related to this field of study and has continued dedicated research within her mentor's lab in preparation for this proposal. This career development program will facilitate her growing expertise in immunology within vascular disease, particularly as this relates to abdominal aortic aneurysms (AAA). The mentor, Dr. Neal Weintraub is an NIH funded investigator on AAAs and has significant expertise in immunology, lipid metabolism, oxidative stress, and adipocyte biology. All of these are ideally suited to the experimental plan. To enhance her career development and research training, the applicant has solicited the assistance of three advisors. Drs. Patrick Tso and Charles "Skip" Smith have known the Applicant for several years and have already been providing mentorship. The applicant has augmented her application with adding Dr. David Hui, from the Metabolic Diseases Institute, given his related expertise, successful mentorship history, and local position. As a part of the career development plan, the applicant will pursue formal coursework specifically needed for the Applicant's project, career growth, and future directions. AAA disease is a frequent cause of morbidity and mortality in older individuals and accounts for over 13,000 deaths and 25,000 surgical repairs in the United States annually. Unlike atherosclerosis, little is known about the specific mechanisms that underlie aneurysm formation, and there is no known effective medical therapy. Surgical and interventional options are limited by complex aneurysm morphology, patient co-morbidities, and post-operative complications. The proposed research will focus on the CD14 receptor in AAA formation where the Applicant has preliminary data to show that CD14 is necessary for AAA formation (unlike in atherosclerosis). Her research since the original submission provides additional mechanistic data linking IL-6, a key cytokine in AAA formation, to CD14 expression on monocytes. Herein, she proposes a series of experiments further investigating the roles of LPS, high fat diet, gut microbiota, and the contributions of specific myeloid cell populations to AAA formation. This important and novel research offers promise for potential therapeutic options in a disease process for which no medical treatment exists. The University of Cincinnati, Department of Emergency Medicine, Division of Cardiovascular Diseases, and Cincinnati Children's offer an ideal setting for mentorship, faculty expertise, resources, training opportunities, K-award and research experience necessary to synergize with the applicant's drive to be a productive, funded researcher.
Abdominal aortic aneurysm (AAA) disease is a frequent cause of morbidity and mortality in older individuals, accounting for 25,000 surgical repairs and 13,000 deaths annually. Unlike in a related disease, atherosclerosis, mechanisms behind AAA formation and growth are not completely understood and no effective medical therapy exists.
|Manka, David; Chatterjee, Tapan K; Stoll, Lynn L et al. (2014) Transplanted perivascular adipose tissue accelerates injury-induced neointimal hyperplasia: role of monocyte chemoattractant protein-1. Arterioscler Thromb Vasc Biol 34:1723-30|
|Blomkalns, Andra L; Gavrila, Daniel; Thomas, Manesh et al. (2013) CD14 directs adventitial macrophage precursor recruitment: role in early abdominal aortic aneurysm formation. J Am Heart Assoc 2:e000065|