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The unique role of B-Raf in murine cardiac development and postnatal function

B-Raf 在小鼠心脏发育和产后功能中的独特作用

基本信息

批准号：
9313924
负责人：
Natasha N Chattergoon
金额：
$ 17.28万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9313924
关键词：
Address Adrenergic Agents Adult Affect Animal Model Animals Apoptosis Appointment Area BRAF gene Biochemical Birth Bone Marrow Calcitonin Gene-Related Peptide Cardiac Cardiac Myocytes Cardiac development Cardiology Cardiomegaly Cardiovascular Diseases Cell Cycle Regulation Chronic Clinical Research Communication Complement Consultations Cutaneous Cyclic AMP Development Doctor of Philosophy Educational process of instructing Environment Exhibits FRAP1 gene Faculty Fetal Development Fetal Heart Fetus Funding Future Genes Genetic Genetic Models Goals Grant Growth Growth Factor Health Health Sciences Heart Heart Research Human Hypertrophy Hypoxia Impairment In Vitro Infusion procedures Institutes Institution Insulin-Like Growth Factor I Interdisciplinary Study Isoproterenol Knockout Mice Knowledge Laboratories Leadership Life Link Lung Malignant Neoplasms Malignant neoplasm of thyroid Mammals Manuscripts Measurement Measures Medical center Mentorship Methods Mitogen-Activated Protein Kinases Mitotic Activity Modeling Modification Molecular Morphology Mus Muscle Cells Mutate Mutation Myocardium Newborn Infant Operative Surgical Procedures Oregon Pathway interactions Performance Perinatal Pharmacology Phase Phenylephrine Physiology Population Positioning Attribute Preparation Primary Cell Cultures Process Proliferating Protein Analysis Protein Isoforms Ras/Raf Rattus Recording of previous events Regulation Renaissance Renal carcinoma Reperfusion Injury Research Research Activity Research Assistant Research Personnel Research Project Grants Resources Risk Role Scientist Sheep Signal Pathway Signal Transduction Signaling Molecule Stress Stromal Cells Syndrome Techniques Testing Time Tissues Training Transfection Transgenic Model United States Department of Veterans Affairs Universities Vascular Smooth Muscle Vasodilator Agents Western Blotting Wild Type Mouse Work cardiogenesis cardiovascular imaging career career development cell growth experience fetal fetal programming heart function hemodynamics human disease in utero in vivo inhibitor/antagonist insight interest melanoma mouse model post-doctoral training postnatal pressure prevent primary pulmonary hypertension professor programs raf Kinases regenerative response stressor vascular smooth muscle cell proliferation

项目摘要

DESCRIPTION (provided by applicant): 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. (End of Abstract)

候选人：Dr. Chattergoon, m.s., Ph.D.我的长期职业目标是建立一个强大的多学科研究项目，利用适当的发展模型，重点了解未来心血管疾病的风险。我的五年职业目标是成为围产期心脏成熟领域的独立研究者，特别是了解控制心脏发育这一阶段的信号机制。我分别于2000年8月和2004年8月在杜兰大学药学系完成了硕士和博士学位。我的博士论文研究的是原发性肺动脉高压背景下血管平滑肌的生长。该领域的研究提供了主动脉和主动脉原代细胞培养的培训