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Function of FNDC3B in cardiovascular and pulmonary development

FNDC3B 在心血管和肺部发育中的功能

基本信息

批准号：
7886278
负责人：
GRANT R MACGREGOR
金额：
$ 19.13万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7886278
关键词：
ABCA3 gene Acute Adherens Junction Adult Affect Affinity Chromatography Alveolus Anatomy Animals Basic Science Binding Binding Sites Birth Blood Vessels Breathing Cardiac Cardiovascular Physiology Cardiovascular system Caveolae Cell Line Cell secretion Cell-Cell Adhesion Cells Consensus Control Animal Coronary Databases Defect Development Diagnosis Disease Economic Burden Electron Microscopy Embryo Embryonic Development Endothelial Cells Epithelial Epithelial Cells Epitopes Eukaryota Exposure to Face Family Fibronectins Functional disorder Goals Healthcare Systems Heart Heart Atrium Histopathology Homeostasis Hour Human Incidence Infection Injury Intercellular Junctions Knowledge Life Light Location Lung Mammals Mass Spectrum Analysis Mediating Membrane Membrane Proteins Methods Molecular Morbidity - disease rate Morphology Mus Muscle Cells Mutant Strains Mice Myocardial Newborn Infant Organelles Pattern Placenta Process Proline Proteins Research Respiratory distress Respiratory physiology Screening procedure Secretory Vesicles Subcellular Anatomy System Tertiary Protein Structure Testing Tight Junctions Tissues Umbilical vein Vascular Endothelial Cell Vascular Endothelial Growth Factor Receptor-2 Ventricular Septal Defects Weibel-Palade Bodies Wild Type Mouse Work airway epithelium alveolar lamellar body base cadherin 5 cardiogenesis environmental allergen human morbidity improved lung development lung maturation member mortality mouse development mutant novel protein expression protein function public health relevance pulmonary function research study surfactant

项目摘要

DESCRIPTION (provided by applicant): Human cardiovascular and pulmonary dysfunction is often life threatening and generates a huge economic burden. Such conditions can arise from abnormal development, or post-natal, from infection, acute injury or exposure to environmental allergen. The high incidence of these conditions provides a clear rationale for long- term basic research to understand the molecular basis for normal development and homeostasis of cardiovascular and pulmonary systems. The long-term goal of this research is to understand the function of the novel protein fibronectin type-III domain containing 3B (FNDC3B) in mammalian cardiovascular and pulmonary development and homeostasis. Fndc3b is expressed in cardiovascular and pulmonary systems and mice mutant for Fndc3b display respiratory distress and die shortly after birth. The cardiovascular system of Fndc3b mice is malformed and hearts display ventricular septal defects and non-compaction. Lung development is also affected and the conducting airway epithelium has abnormal morphology. FNDC3 proteins contain a highly conserved consensus binding site for WW-domain containing proteins. Based on these, and additional, findings we hypothesize that FNDC3B functions in pulmonary epithelial cells, and in vascular endothelial cells to modulate cell-cell adhesion required for normal pulmonary and cardiovascular function. We also hypothesize that FNDC3B is required for secretion of surfactant and that FNDC3B accomplishes each of these functions by binding to specific WW-domain containing proteins. To test these hypotheses, three sets of experiments are proposed. First, we will identify which cells express FNDC3B in the lung and heart of mice. Second, we will analyze the anatomy and function of epithelial cells lining the bronchiolar airway and alveoli and investigate whether the expression of proteins required for normal pulmonary function is affected in Fndc3b mutant and control animals. We shall also investigate whether cell- cell junctions are intact, and if unique secretory organelles required for normal function of airway epithelial cells, atrial myocytes and vascular endothelial cells such as lamellar bodies, secretory granules, caveolae and Weibel-Palade bodies are abnormal in Fndc3b mutant animals. Third, we will investigate which WW-proteins interact with FNDC3B using (a) an array based method and (b) by tandem-affinity purification of epitope- tagged FNDC3B expressed in mouse airway epithelial MEL15 cells and HUVEC endothelial cells followed by mass spectrometry and database analysis. These studies will provide new information about the function of FNDC3B in cardiovascular and pulmonary development in mice. The long-term benefit of this basic research will be to improve our knowledge of the molecular and cellular basis for cardiovascular and pulmonary development and homeostasis, which in turn will offer new opportunities for diagnosis, and ultimately treatment, of human conditions associated with dysfunction of these essential systems. PUBLIC HEALTH RELEVANCE: Abnormal cardiovascular and lung function in newborn infants is a common cause of morbidity and mortality that generates significant human suffering, and financial burden on the health-care system. Understanding the causes of these disorders is an important step towards the long- term goals of improved diagnosis and treatment for such conditions. We are investigating the function of a novel protein, FNDC3B, which is required for normal heart and lung development and post-natal survival of mice. The long-term benefit of this basic research will be to increase our knowledge of the molecular and cellular basis for cardio-pulmonary development in mammals, which in turn will offer improved diagnosis, and ultimately treatment, of human conditions associated with abnormal cardiovascular and pulmonary function.