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

描述（由申请人提供）：这是一个指导培训计划的建议，旨在发展转化心肺研究的学术生涯。候选人已成功地完成了临床和研究奖学金在儿科重症监护医学在加州大学弗朗西斯科分校（UCSF），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计划，利用著名的，多学科的环境提供的心血管研究所（CVRI）在UCSF。 候选人将利用综合方法来解决与先天性心脏病和肺血流量（PBF）增加相关的肺液稳态机制。导师杰弗里·R Fineman，医学博士，是加州大学旧金山分校CVRI的儿科教授和研究员。他是一位国际公认的肺血管疾病专家，并有着非常强大的成功指导历史。此外，一个由杰出的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关键的科学审查：Michael Matthay博士、Donald McDonald博士和达拉斯Hyde博士分别以其在肺水和肺损伤、肺组织学以及体视学和肺结构领域的专业知识而闻名于世。 该研究计划旨在阐明与常见先天性心脏病相关的PBF增加背景下肺液稳态的机制。利用独特的、临床相关的先天性心脏病伴PBF增加的绵羊模型（在子宫内通过经皮放置的肺动脉移植物产生），我们已经产生了体内数据，表明慢性增加的PBF与（1）受损的相对淋巴流量，（2）降低的生物可利用的一氧化氮，（3）延迟的通过肺动脉的转运动力学，（4）淋巴结构的畸变，和（5）与淋巴生长相关的蛋白质如血管内皮生长因子-C表达的改变。基于这些发现，我们的总体假设是，慢性PBF增加导致肺淋巴管内皮功能受损，导致淋巴流动和出生后发育的扰动。通过整合整体动物实验、器官实验、分子实验、离体血管实验、细胞培养实验和生物化学实验，本研究旨在完成以下任务：描述PBF慢性增加对肺液体平衡的影响，并阐明控制这些变化的机制。特别是，调节肺淋巴管功能和出生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.