Therapeutic Potential of ALK1 Activating Drugs in HHT Models

项目总结/摘要（描述） 遗传性出血性毛细血管扩张症（HHT）是一种常染色体显性遗传病，其特征是： 在几个器官中以动静脉形式出现可能危及生命的血管异常 畸形（AVM）。HHT突变主要存在于ALK 1和ENG基因中，并导致 在BMP 9/10-ALK 1-ENG信号级联中发挥作用。有证据表明HHT是由异常的 再活化血管生成和内皮细胞（EC）驱动的过度血管形成。这个项目的总体目标是 该计划是实施一项旨在识别FDA批准的药物的筛选和表征策略 在HHT的新型细胞和小鼠模型中具有疾病修饰特性和治疗潜力。我们 已经筛选了美国国立卫生研究院临床收集的FDA批准的药物，以确定能够激活 报告细胞中的ALK 1信号传导。亲免素配体他克莫司（FK 506）被鉴定为最有效的 ALK 1激活剂。在初步研究中，我们证实他克莫司及其类似物西罗莫司是有效的 EC中的ALK 1信号传导激活剂。重要的是，这两种类似物药物预防了视网膜血管病变， BMP 9/10免疫阻断的经乳房模型，是我们最近开发的HHT小鼠模型， 实验室此外，我们确定他克莫司有效地触发了原代EC中ALK 1的激活， 来源于携带已充分描述的致病ALK 1-T372 fsX突变的HHT患者。基于 根据这些结果，我们在本申请的目的1和2中提出评估和比较 他克莫司和西罗莫司在BMP 9/10免疫阻断的经乳房模型中的作用，以及在一种新的敲入模型中的作用。 表达HHT ALK 1-T372 fsX突变的小鼠系。我们还将建立一个HHT患者的迷你银行- 衍生的初级EC，将用于描述他克莫司和西罗莫司 控制ALK 1信号传导（Aim 3）。我们认为，在相关和强大的模型中， HHT的研究不仅将增加我们对疾病分子基础的理解， 推动HHT的新临床研究。

PROJECT SUMMARY/ABSTRACT (DESCRIPTION) Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder characterized by the development of potentially life-threatening vascular anomalies in several organs in the form of arteriovenous malformations (AVMs). HHT mutations are mostly found in the ALK1 and ENG genes and lead to a loss-of- function in the BMP9/10-ALK1-ENG signaling cascade. Evidence suggests that HHT arise from aberrant reactivation of angiogenesis and endothelial cell (EC)-driven hypervascularization. The overall goal of this program is to implement a screening and characterization strategy aimed at identifying FDA-approved drugs with disease-modifying properties and therapeutic potential in novel cellular and mouse models of HHT. We have screened the NIH clinical collections of FDA-approved drugs to identify molecules capable of activating ALK1 signaling in reporter cells. The immunophilin ligand tacrolimus (FK506) was identified as the most potent ALK1 activator. In preliminary studies, we confirmed that tacrolimus, as well as its analog sirolimus, are potent ALK1 signaling activators in ECs. Of significance, the two analog drugs prevented retinal vascular pathology in the transmammary model of BMP9/10-immunoblocking, an HHT mouse model recently developed in our laboratory. In addition, we determined that tacrolimus efficiently triggered ALK1 activation in primary ECs derived from an HHT patient carrying the well-described disease-causing ALK1-T372fsX mutation. Based on these results, we propose in Aims 1 and 2 of this application to assess and compare the therapeutic potential of tacrolimus and sirolimus in the transmammary model of BMP9/10-immunoblocking and in a new knockin mouse line expressing the HHT ALK1-T372fsX mutation. We will also generate a mini-bank of HHT patient- derived primary ECs, which will be used to delineate the mechanisms by which tacrolimus and sirolimus control ALK1 signaling (Aim 3). We believe that this comprehensive approach in relevant and powerful models of HHT not only will increase our understanding of the molecular underpinnings of the disease, but also will motivate new clinical investigations for HHT.