Investigation of hepatic factor in pulmonary arteriovenous malformations

项目总结 在K08申请中提出的研究将使用创新的方法来研究可溶性血管 内皮生长因子受体1(SVEGFR1)是肺微血管重构的重要调节因子 和肺动静脉畸形(PAVM)发展的抑制剂。血管内皮细胞生长 血管内皮细胞生长因子(VEGFs)信号转导是血管萌发和血管动态平衡所必需的。如果不进行检查， 血管内皮生长因子信号也可导致血管不稳定和病理性重构。抑制血管内皮细胞生长因子信号转导 多个血管床可以使现有的动静脉动静脉畸形正常化，补充sVEGFR1可以预防脑动静脉畸形。 利用患者的血液样本，我们最近发现sVEGFR1在肝静脉中显著升高 可能是单室先天性心脏病患者PAVM形成的潜在抑制因素 疾病。这项建议的目的将通过检查患者的血液来直接检验我们的初步观察 并检测sVEGFR1在体外、体外和体内对肺微血管系统的影响。 这项建议的目的是推进对单室先天性心脏病患者的护理 心脏病和呼吸机疾病。这些目标也将提高我们对肺微血管的理解 生物学。 K08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 进一步发展在体外和体外操纵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构。vbl.使用 在体外修改变量和探索临床问题的分子生物学工具将使我能够 作为一名内科科学家，实现这项建议的目标并解决未来的新问题。 其次，我将获得新的技能和经验，使用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，如 以及利用临床技能修改动物生理学，将使我能够独立研究临床 有问题。具有先进的实验技术经验，如精切肺切片、离体肺 灌注和下一代测序(rna-seq和单细胞rna-seq)将使我能够测试 具有创新的科学方法的假设。最后，作为一名内科科学家，这些技能将使我 与我的机构内外的研究人员合作，推动团队科学的发展。

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.