Therapeutic Potential of ALK1 Activating Drugs in HHT Models

项目摘要/摘要(说明) 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 几个器官的动静脉形式的潜在危及生命的血管异常的发展 畸形(Avm)。HHT突变主要在ALK1和ENG基因中发现，并导致- 在BMP9/10-ALK1-ENG信令级联中发挥作用。有证据表明，高血压是由异常引起的 血管生成的重新激活和内皮细胞(EC)驱动的血管过度血管化。这个项目的总体目标是 该计划是实施旨在识别FDA批准的药物的筛选和表征战略 在新的HHT细胞和小鼠模型中具有疾病修改特性和治疗潜力。我们 对NIH临床收集的FDA批准的药物进行了筛选，以确定能够激活的分子 报告细胞中的ALK1信号。免疫亲和素配体他克莫司(FK506)被认为是最有效的 ALK1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。 内皮细胞中的ALK1信号激活物。有意义的是，这两种类似药物预防视网膜血管病变 新近建立的HHT小鼠BMP9/10免疫阻断模型 实验室。此外，我们还确定他克莫司有效地激活了原代内皮细胞中的ALK1 来自一名携带有众所周知的致病基因ALK1-T372fsX突变的HHT患者。基于 这些结果，我们建议在本申请的目标1和2中评估和比较治疗潜力。 他克莫司和西罗莫司在BMP9/10免疫阻断模型中的作用及一种新的敲门方式 表达HHTALK1-T372fsX突变的小鼠株系。我们还将创建一个HHT患者的迷你库- 衍生的原代内皮细胞，将用于描述他克莫司和西罗莫司的作用机制 控制ALK1信号(目标3)。我们认为，在相关和强大的模式中，这种全面的方法 HHT的研究不仅将增加我们对疾病分子基础的了解，而且还将 推动新的HHT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.