Altered Lymphatics in an Ovine Cardiac Model of Increased Pulmonary Blood Flow

肺血流量增加的绵羊心脏模型中淋巴管的改变

基本信息

批准号：
8581784
负责人：
Sanjeev A. Datar
金额：
$ 13.39万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8581784
关键词：
Acute Address Advisory Committees Angiopoietin-2 Animal Organ Architecture Bioavailable Biochemical Blood Vessels Blood capillaries Blood flow California Cardiac Cardiopulmonary Cardiovascular system Cell Culture Techniques Child Childhood Chronic Clinical Clinical Research Congenital Heart Defects Critical Care Cyclic GMP Data Defect Dehydration Development Diuretics Doctor of Medicine Electrolytes Endothelium Environment Exposure to Fellowship Filtration Fluid Balance Functional disorder Growth Growth and Development function Homeostasis Impairment In Vitro Infant Intervention Investigation Kinetics Lead Life Liquid substance Lung Lymph Lymphatic Lymphatic Endothelial Cells Lymphatic System Lymphatic vessel Lymphography Mediating Medical Medicine Mentors Mentorship Metabolic Modeling Molecular Morbidity - disease rate Nitric Oxide Nitric Oxide Signaling Pathway Palliative Surgery Patients Pediatrics Pharmaceutical Preparations Physiological Play Post-Translational Protein Processing Process Proteins Reactive Oxygen Species Recording of previous events Regulation Relative (related person)Research Research Institute Research Personnel Respiratory Mechanics Respiratory physiology Role San Francisco Sheep Shunt Device Signal Pathway Signal Transduction Structure Superoxides Symptoms Testing Therapeutic Thoracic Duct Time Training Programs Universities Vascular Diseases Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Water antioxidant therapy base capillary career clinically relevant congenital heart disorder design experience in utero in vivo inhaled nitric oxide lung injury lymph flow lymphatic circulation mRNA Expression mortality multidisciplinary novel polyethylene glycol-superoxide dismutase postnatal pressure professor programs protein expression public health relevance research study respiratory response shear stress skills

项目摘要

DESCRIPTION (provided by applicant): This is a proposal for a mentored training program designed to develop an academic career in translational cardiopulmonary research. The candidate has successfully completed a clinical and research fellowship in Pediatric Critical Care Medicine at the University of California, San Francisco (UCSF), and is now prepared to fully develop and refine skills necessary to sustain an independent research program, utilizing the renowned, multidisciplinary environment offered by the Cardiovascular Research Institute (CVRI) at UCSF. The candidate will utilize an integrated approach to address mechanisms of lung fluid homeostasis associated with congenital heart defects and increased pulmonary blood flow (PBF). The mentor, Jeffrey R. Fineman, M.D., is Professor of Pediatrics and Investigator in the CVRI at UCSF. He is an internationally recognized expert on pulmonary vascular disease, and has an extremely strong history of successful mentorship. In addition, an advisory committee of distinguished biomedical investigators will provide critical scientific review on key aspects of this proposal: Drs. Michael Matthay, Donald McDonald, and Dallas Hyde are world-renowned for their expertise in the field of lung water and lung injury, lung lymphatics, and stereology and lung structure, respectively. The research plan seeks to elucidate the mechanisms underlying lung fluid homeostasis in the context of increased PBF that is associated with common congenital heart defects. Utilizing a unique, clinically relevant ovine model of a congenital heart defect with increased PBF (created in utero by a surgically-placed aortopulmonary graft), we have generated in vivo data indicating that chronically increased PBF is associated with (1) impaired relative lymphatic flow, (2) decreased bioavailable nitric oxide, (3) delayed transit kinetics through the pulmonary lymphatics, (4) aberrations in lymphatic architecture, and (5) alterations in the expression of proteins associated with lymphatic growth, such as vascular endothelial growth factor-c. Based on these findings, our overall hypothesis is that chronically increased PBF leads to impaired pulmonary lymphatic endothelial function, resulting in perturbation in lymphatic flow and postnatal development. By integrating whole animal, organ-based, molecular, isolated vessel, cell-culture, and biochemical experiments, this proposal seeks to accomplish the following: to characterize the effects of chronic increases in PBF on lung fluid balance, and to elucidate the mechanisms controlling these changes. In particular, the signaling pathways that regulate pulmonary lymphatic vascular function and post-natal lymphatic growth and remodeling will be examined.

描述（由申请人提供）：这是一项指导培训计划的建议，旨在发展转化心肺研究的学术职业。这位候选人已成功完成了加州大学旧金山大学（UCSF）儿科重症监护医学的临床和研究奖学金，现在准备充分发展和完善所需的技能，利用著名的多学科，由CVRI（CVRI）提供的著名，多学科的环境。候选人将利用一种综合方法来解决与先天性心脏缺陷相关的肺部稳态和肺部血流增加（PBF）的机制。导师Jeffrey R. Fineman，医学博士是UCSF CVRI的儿科和研究人员。他是国际公认的肺血管疾病专家，并且拥有成功的指导历史。此外，杰出的生物医学研究人员的咨询委员会将对该提案的关键方面提供重要的科学审查：DRS。迈克尔·马特（Michael Matthay），唐纳德·麦克唐纳（Donald McDonald）和达拉斯·海德（Dallas Hyde）因其在肺水和肺部损伤，肺淋巴管以及立体和肺结构方面的专业知识而受到世界知名。该研究计划旨在在PBF增加的背景下阐明与常见先天性心脏缺陷有关的机制。利用PBF增加的先天性心脏缺陷的独特，临床相关的卵巢模型（在子宫内通过手术放置的主动脉肺移植物在子宫内创建），我们已经在体内数据中产生了PBF的慢性增长，表明PBF与（1）相对淋巴流动（2）延迟（2）延迟（2）延迟（2）延伸（2），KIN-KINOMAID（3）淋巴管，（4）淋巴结构中的畸变，以及（5）与淋巴生长相关的蛋白质表达的改变，例如血管内皮生长因子-C。基于这些发现，我们的总体假设是，长期增加的PBF导致肺淋巴内皮功能受损，从而导致淋巴流和产后发育的扰动。通过整合整个动物，基于器官的，分子，孤立的血管，细胞培养和生化实验，该建议旨在完成以下方面：表征PBF慢性增加对肺液平衡的影响，并阐明控制这些变化的机制。特别是，将检查调节肺淋巴管功能和产后淋巴生长和重塑的信号通路。