Investigation of hepatic factor in pulmonary arteriovenous malformations

项目摘要 本K 08申请中的拟议研究将使用创新方法研究可溶性血管 内皮生长因子受体1（sVEGFR 1）作为肺微血管重构的关键调节因子 和肺动静脉畸形（PAVM）发展的抑制剂。血管内皮生长 因子（VEGF）信号传导对于萌芽血管生成和血管稳态是不可或缺的。如果不加检查， VEGF信号传导还可导致血管不稳定和病理性重塑。抑制VEGF信号转导， 多个血管床可以使现有的AVM正常化，补充sVEGFR 1可以预防脑AVM。 我们最近发现，使用患者的血液样本，sVEGFR 1在肝静脉中显著升高， 可能是单心室先天性心脏病患者PAVM形成的潜在抑制剂 疾病这项建议的目的是通过检查病人的血液来直接检验我们的初步观察结果 样品，并在体外、离体和体内测试sVEGFR 1对肺微血管的作用。 该提案的目的是促进单心室先天性心脏病患者的护理的先决条件， 心脏病和PAVM。这些目标也将提高我们对肺微血管的理解 生物学 K 08应用程序中的培训计划将支持我的职业发展，主要有两个目标。首先我会 进一步发展体外和离体操作患者来源和生物相关组织的专业知识， 研究肺内皮细胞基因表达、血管生成和微血管重塑。使用 分子生物学工具，以修改变量在体外和探测临床导向的问题，将使我能够 实现这一建议的目标，并解决新的问题，在未来作为一个物理学家，科学家。 其次，我将获得新的技能和经验，与转基因动物模型和创新 研究肺微血管的技术。熟练使用现代转基因动物模型的能力， 以及利用临床技能来改变动物生理学，将使我能够独立研究临床 问题具有先进的实验技术经验，如精密肺切片、离体肺 灌注，和下一代测序（RNA-seq和单细胞RNA-seq），将允许我测试 创新的科学方法。最后，作为一名医生和科学家， 我很高兴与当地和机构外的研究人员合作，以推进团队科学。

PROJECT SUMMARY The proposed studies in this K08 application will use innovative approaches to investigate soluble vascular endothelial growth factor receptor 1 (sVEGFR1) as a critical regulator of pulmonary microvascular remodeling and inhibitor of pulmonary arteriovenous malformation (PAVM) development. Vascular endothelial growth factor (VEGF) signaling is integral to sprouting angiogenesis and vascular homeostasis. If left unchecked, VEGF signaling can also lead to vascular instability and pathologic remodeling. Inhibiting VEGF signaling in multiple vascular beds can normalize existing AVMs, and supplemental sVEGFR1 can prevent brain AVMs. Using patient blood samples, we recently identified that sVEGFR1 is significantly elevated in hepatic vein serum and may be a potential inhibitor of PAVM formation in patients with univentricular congenital heart disease. The aims of this proposal will directly test our preliminary observation by examining patient blood samples and testing the effects of sVEGFR1 on the pulmonary microvasculature in vitro, ex vivo, and in vivo. The aims of this proposal are prerequisites to advancing the care of patients with univentricular congenital heart disease and PAVMs. These aims will also improve our understanding of pulmonary microvascular biology. The training plan in this K08 application will support my career development with two main goals. First, I will further develop expertise manipulating patient-derived and biologically relevant tissues in vitro and ex vivo to investigate lung endothelial cell gene expression, angiogenesis, and microvascular remodeling. Using molecular biology tools to modify variables in vitro and probe clinically oriented questions will allow me to achieve the objectives of this proposal and address new questions in the future as a physician-scientist. Second, I will acquire new skills and experience working with transgenic animal models and innovative techniques to study the lung microvasculature. The ability to adeptly use modern transgenic animal models, as well as leverage clinical skills to modify animal physiology, will position me to independently investigate clinical problems. Experience with advanced experimental techniques, such as precision cut lung slices, isolated lung perfusion, and next-generation sequencing (RNA-seq and single cell RNA-seq), will allow me to test hypotheses with innovative scientific approaches. Finally, as a physician-scientist these skills will position me well to collaborate with investigators locally and outside my institution to advance team science.