Cell type-specific influences on HHT pathogenesis

细胞类型特异性对 HHT 发病机制的影响

• 批准号: 8995684
• 负责人: HUA SU
• 金额: $ 39.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-16 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8995684
• 关键词: ACVRL1 gene; Activins; Adult; Arteriovenous malformation; Blood; Blood Vessels; Blood specimen; Bone Marrow; Bone Marrow Stem Cell; Brain; Cell Lineage; Cells; Clonal Expansion; Complex; Data; Development; Disease Progression; Dose; Dysplasia; ENG gene; Endoglin; Endothelial Cells; Environmental Risk Factor; Gene Deletion; Gene Mutation; Genes; Genotype; Health; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hemorrhage; Hereditary hemorrhagic telangiectasia; Homing; Human; Inflammation; Inflammatory; Injury; Intestines; Investigation; Knowledge; Latex; Lead; Lesion; Life; Lung; Measures; Mediating; Medical; Mesenchymal; Modeling; Muramidase; Mus; Mutate; Mutation; Organ; Organoids; PTPRC gene; Pathogenesis; Patients; Phenotype; Phosphotransferases; Positioning Attribute; Radio; Recurrence; Resistance; Role; Severities; Signal Pathway; Site; Skin; Specificity; Stem cells; Stream; Stromal Cells; Telangiectasis; Testing; Therapeutic; Transforming Growth Factors; Transfusion; Transplantation; University Hospitals; Validation; Variant; Vascular Endothelial Growth Factors; Wild Type Mouse; angiogenesis; bone morphogenic protein; brain arteriovenous malformations; cell type; design; disability; loss of function; loss of function mutation; macrophage; monocyte; mouse model; mutant; novel; novel therapeutics; pre-clinical trial; receptor; research study; ACVRL1 gene; Activins; Adult; Arteriovenous malformation; Blood; Blood Vessels; Blood specimen; Bone Marrow; Bone Marrow Stem Cell; Brain; Cell Lineage; Cells; Clonal Expansion; Complex; Data; Development; Disease Progression; Dose; Dysplasia; ENG gene; Endoglin; Endothelial Cells; Environmental Risk Factor; Gene Deletion; Gene Mutation; Genes; Genotype; Health; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hemorrhage; Hereditary hemorrhagic telangiectasia; Homing; Human; Inflammation; Inflammatory; Injury; Intestines; Investigation; Knowledge; Latex; Lead; Lesion; Life; Lung; Measures; Mediating; Medical; Mesenchymal; Modeling; Muramidase; Mus; Mutate; Mutation; Organ; Organoids; PTPRC gene; Pathogenesis; Patients; Phenotype; Phosphotransferases; Positioning Attribute; Radio; Recurrence; Resistance; Role; Severities; Signal Pathway; Site; Skin; Specificity; Stem cells; Stream; Stromal Cells; Telangiectasis; Testing; Therapeutic; Transforming Growth Factors; Transfusion; Transplantation; University Hospitals; Validation; Variant; Vascular Endothelial Growth Factors; Wild Type Mouse; angiogenesis; bone morphogenic protein; brain arteriovenous malformations; cell type; design; disability; loss of function; loss of function mutation; macrophage; monocyte; mouse model; mutant; novel; novel therapeutics; pre-clinical trial; receptor; research study

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.

描述（由适用提供）：在院中出血性毛细血管扩张（HHT）中，多个器官和telangiectia中的动静脉畸形（AVM）是导致复发赞助者的主要病变病变，并导致长期的残疾。一个普遍的观点是，HHT是由单倍不足引起的 其严重基因之一的体细胞内皮细胞（EC），例如HHT1或ALK1（ACVLR1，TGFß/BMP的TGFß/BMP的辅助受体），HHT2中的TGFß/BMP的1型受体。然而，我们和其他人的研究表明，仅体细胞EC中的基因单倍不足是不足以解释AVM的发展和进展以及HHT表型的变化。取而代之的是，我们的数据支持以下几个因素的相互作用导致AVM发展和进展的假设：（1）EC中ENK或ALK1的剂量依赖性纯合功能丧失； （2）源自造血干细胞（HSC）的EC和巨噬细胞的贡献； （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，从而复制了人类HHT表型。我们将使用来自多伦多大学圣迈克尔医院HHT中心提供的HHT患者的这些模型和血液标本来检验这些假设。在AIM 1中，我们将使用HHT1和HHT2小鼠模型以及新型的肺器官模型来确定器官之间AVM形成所需的Eng或Alk1-Null EC的数量是否不同，并且与病变严重程度呈正相关。在AIM 2中，我们将使用HSC移植实验来确定HSC衍生的ALK1或ENG-NULL EC的作用以及巨噬细胞在AVM计划和进展中的作用。在AIM 3中，我们将使用HHT患者的小鼠模型和血液单核细胞来研究HHT单核细胞和巨噬细胞如何促进AVM的进展。该项目将是AVM形成和进展中涉及的细胞类型的首次系统投资。我们特定目标的实现将导致我们对HHT患者中AVM的理解的理解。我们提出的研究的结果将导致对HHT中AVM发病机理的基本机制的全面了解，并使我们处于设计特定疗法的更好位置。在该项目中测试的机制的验证可以导致可以在临床前试验中测试的潜在疗法。这对于该领域来说将是一个重大进步，因为HH患者的治疗选择目前非常有限。