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

描述（由申请人提供）：这是一份指导培训计划的提案，旨在发展转化心肺研究的学术生涯。该候选人已成功完成加州大学旧金山分校（UCSF）儿科重症医学的临床和研究奖学金，现在准备充分发展和完善必要的技能，以维持一个独立的研究项目，利用UCSF心血管研究所（CVRI）提供的著名的多学科环境。该候选人将利用综合方法解决与先天性心脏缺陷和肺血流量增加（PBF）相关的肺液稳态机制。导师Jeffrey R. Fineman，医学博士，是加州大学旧金山分校儿科教授和CVRI研究员。他是国际公认的肺血管疾病专家，并拥有非常强大的成功指导历史。此外，一个由杰出生物医学研究人员组成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。Michael Matthay、Donald McDonald和Dallas Hyde分别在肺水和肺损伤、肺淋巴学、体视学和肺结构领域拥有世界知名的专业知识。该研究计划旨在阐明与常见先天性心脏缺陷相关的PBF增加背景下肺液稳态的机制。利用一种独特的临床相关的先天性心脏缺陷羊模型，PBF增加（通过手术放置的主动脉肺移植物在子宫内产生），我们产生了体内数据，表明长期增加的PBF与(1)相对淋巴血流受损，(2)生物可用性一氧化氮减少，(3)通过肺淋巴管的运输动力学延迟，(4)淋巴结构畸变，(1)相对淋巴血流受损有关。(5)淋巴管生长相关蛋白表达的改变，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，导致淋巴流动和出生后发育的紊乱。通过整合全动物实验、器官实验、分子实验、离体血管实验、细胞培养实验和生化实验，本研究旨在研究PBF慢性升高对肺液平衡的影响，并阐明控制这些变化的机制。特别是，调节肺淋巴血管功能和产后淋巴生长和重塑的信号通路将被检查。

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.