Candidate: Dr. Chattergoon, M.S., Ph.D. My long-term career objective is to build a strong multidisciplinary research program, utilizing appropriat developmental models that focus on understanding the risks of future cardiovascular disease. My five-year career goal is to become an independent investigator in the area of cardiac maturation in the perinatal period and especially understanding the signaling mechanisms that govern this phase of heart development. I completed my M.S. and Ph.D. degrees at Tulane University in the Department of Pharmacology in August 2000 and August 2004, respectively. I studied vascular smooth muscle growth in the context of primary pulmonary hypertension for my doctoral dissertation. This area of research offered training in primary cell culture of aortic and pulmonary vascular smooth muscle cells (VSMC), protein analysis by western blot, immunostaining, adenoviral gene transfection, and primary bone marrow stromal cell characterization. We determined that calcitonin gene-related peptide, a powerful vasodilator, is potent inhibitor of VSMC proliferation in vitro by stimulating cAMP pathways that affect cell cycle regulation. I began my postdoctoral training in Dr. Kent L. Thornburg's laboratory at Oregon Health and Science University (OHSU) in August of 2004. I joined this laboratory to train in fetal heart development and how changes to the fetal environment dramatically alter heart growth. I have invested the several years required to become facile with the fetal sheep model used in Dr. Thornburg's laboratory. With that came extensive teaching by our collaborators, Drs. G Giraud, S Louey, S Jonker, D Andersen, L Davis, and J Faber. With this group of scientists I have learned the surgical techniques required for chronic fetal studies, methods for continuous hemodynamic measurements, and the general methods of chronic large animal in vivo studies, as well as primary culture of fetal cardiomyocytes. I have also gained great experience in grant and manuscript preparation. I plan to apply what I have learned in large mammal heart development to how genetic perturbations in utero may have detrimental consequences for post-natal life under the new mentorship of Drs. Stork and Van Winkle. My proposed studies will allow me generate and utilize transgenic models in a way that helps to marry my interests in both whole animal physiology as well as molecular signaling in the heart. Also, by using echocardiographic techniques to determine cardiac function in the mouse model I will introduce a new layer to the work already under way Dr. Stork's lab. I will also use various genetic models for my future studies. Attending, presenting and interacting with leaders in cardiac development and signaling are also important aspects of my training. These research activities are essential to my career development in this field. As I transition to my new appointment of Research Assistant Professor I feel I am in the perfect position and at the ideal institution to bridge the gaps of knowledge we have in understanding fetal programming with reference to cardiac development. The funding for this project will also be the basis of setting my long-term goals. Environment: Oregon Health and Science University (OHSU) is especially fertile for developing my research program. Through this proposal I will interact with research teams at Portland Veterans Administration Medical Center, the Vollum Institute, the Biomedical Information Communications Center, the Heart Research Center, and the Cardiovascular Imaging lab. The Division of Cardiology has a strong history of clinical and research excellence and had undergone a renaissance under the leadership of Dr. Sanjiv Kaul. Dr. Kaul has an unwavering commitment to academics and a history of supporting junior faculty scientists. The university has roughly 12 shared Core resources facilities that offer consultation on study analyses and I will be working with 5 of them for this project. Research Project: The fetal period is a critical stage for heart development. In larger mammals, like the sheep, cardiomyocytes gradually cease dividing and become primarily binucleated (terminal differentiation) just prior to birth. Once cardiac myocytes terminally differentiate they can no longer divide but they retain a remarkable capacity to enlarge. In the mouse, cardiomyocytes continue to proliferate and terminally differentiate over the first week of postnatal life. There is a large gap in our understanding of the signaling pathways that yield the proper number of cardiomyocytes at birth. This proposal will address one major portion of that gap. The mitogen activated protein kinase (MAPK) is a major proliferative pathway that is influenced by Ras/Raf-1 signaling. This proposal will examine the role of B-Raf blockade in both genetic models and pharmacological models in the mouse. B- Raf has not been studied in the developing heart. We hypothesize that blockade of B-Raf control of MAPK in cardiomyocytes will alter the proliferative and hypertrophic signals and will provide an animal model with pathophysiological consequences of altered cardiac cell growth. A positive finding would confirm the role of this important signaling molecule and will provide new potential avenues of growth therapy for under grown hearts. We will couple the results of B-Raf disruption to morphological, biochemical, and functional parameters of cardiac performance in the newborn and adult using echocardiographic measures.

Public Health Relevance

Given the limited regenerative capacity of the heart after birth, preventing the full attainment of cardiomyocyte number will have long-term negative consequences. Genetically modifying ERK regulation of this process will lend further understanding of how cardiomyocyte proliferation and differentiation in early development influences postnatal heart function.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Scientist Development Award - Research & Training (K01)
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Special Emphasis Panel (ZHL1-CSR-F (F1))
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Meadows, Tawanna
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Oregon Health and Science University
Internal Medicine/Medicine
Schools of Medicine
United States
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