Cell type-specific influences on HHT pathogenesis

描述（由申请人提供）：在遗传性出血性毛细血管扩张症（HHT）中，多器官动静脉畸形（AVM）和毛细血管扩张症是导致复发性自发性出血的主要病理学病变，可能危及生命并导致长期残疾。流行的观点是HHT是由单倍不足引起的， 其致病基因之一的体细胞内皮细胞（EC），如HHT 1中的内皮糖蛋白（ENG，TGF β 1/BMP的辅助受体）或HHT 2中的ALK 1（ACVLR 1，TGF β 1/BMP的1型受体）。然而，我们和其他人的研究表明，基因单倍不足体细胞EC单独是不足以解释AVM的发展和进展和HHT表型的变化。相反，我们的数据支持以下假设，即AVM的发生和进展是由以下几个因素的相互作用引起的：（1）EC中ENG或ALK 1的剂量依赖性纯合子功能丧失;（2）EC和源自造血干细胞（HSC）的巨噬细胞的作用;（3）HHT单核细胞和巨噬细胞的促炎表型。我们已经开发了几种在多个器官中具有AVM的小鼠模型，复制了人类HHT表型。我们将使用这些模型和多伦多大学圣迈克尔医院HHT中心提供的HHT患者的血液标本来检验这些假设。在目标1中，我们将使用HHT 1和HHT 2小鼠模型和新型肺类器官模型来确定AVM形成所需的Eng-或Alk 1-null EC的数量在器官之间是否不同，并且与病变严重程度呈正相关。在目标2中，我们将使用HSC移植实验来确定HSC衍生的Alk 1或Eng-null EC和巨噬细胞在AVM发生和发展中的作用。在目标3中，我们将使用小鼠模型和HHT患者的血液单核细胞来研究HHT单核细胞和巨噬细胞如何促进AVM进展。该项目将是第一个系统研究AVM形成和进展所涉及的细胞类型。我们特定目标的实现将导致我们对HHT患者中AVM形成方式的理解发生范式转变。我们提出的研究结果将导致对HHT中AVM发病机制的基本机制有更全面的了解，并使我们能够更好地设计特定的治疗方法。验证该项目中测试的机制可以导致可以在临床前试验中测试的潜在疗法。这将是该领域的重大进步，因为HH患者的治疗选择目前非常有限。

DESCRIPTION (provided by applicant): In hereditary hemorrhagic telangiectasia (HHT), arteriovenous malformations (AVMs) in multiple organs and telangiectasia are the major pathological lesions causing recurrent spontaneous hemorrhage that can be life- threatening and leads to long-term disability. A prevailing view is that HHT is caused by haploinsufficiency in somatic endothelial cells (ECs) of one of its causative genes, such as endoglin (ENG, an accessory receptor of TGFß/BMP) in HHT1 or ALK1 (ACVLR1, a type 1 receptor of TGFß/BMP) in HHT2. However, studies by us and others suggest that gene haploinsufficiency in somatic EC alone is inadequate to explain AVM development and progression and the variations in HHT phenotypes. Instead, our data support the hypotheses that AVM development and progression result from an interplay of several factors: (1) a dose-dependent homozygous loss-of-function of ENG or ALK1 in ECs; (2) contribution of EC and macrophage derived from hematopoietic stem cells (HSC); and (3) pro-inflammatory phenotype of HHT monocytes and macrophages. We have developed several mouse models that have AVMs in multiple organs, replicating the human HHT phenotype. We will use these models and blood specimens from HHT patients provided by HHT Center in St. Michael's hospital of University of Toronto to test these hypotheses. In Aim 1 we will use HHT1 and HHT2 mouse models and a novel lung organoid model to determine if the quantity of Eng- or Alk1-null EC required for AVM formation is different among organs and is positive correlate with lesion severity. In Aim 2, we will use HSC transplantation experiments to determine the roles of HSC-derived Alk1- or Eng-null ECs and macrophages in AVM initiation and progression. In Aim 3, we will use both mouse models and blood monocytes from HHT patients to investigate how HHT monocytes and macrophages promote AVM progression. This project will be the first systematic investigation of the cell types involved in AVM formation and progression. The accomplishment of our specific aims will lead to a paradigm shift on our understanding of how AVMs form in HHT patients. The results of our proposed studies will lead to a fuller knowledge of the basic mechanisms of AVM pathogenesis in HHT, and put us in a much better position to design specific therapies. Validation of the mechanisms being tested in this project can lead to potential therapies that can be tested in pre-clinical trials. This would be a significant advance for the field since therapeutic options for HH patients are currently very limited.