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: 8816957
• 负责人: HUA SU
• 金额: $ 39.64万
• 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/8816957
• 关键词: ACVRL1 gene; Adult; Arteriovenous malformation; Blood; Blood Vessels; Blood specimen; Bone Marrow; 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; 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; Positioning Attribute; Radio; Recurrence; Relative (related person); 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; activin receptor-like kinase 1; angiogenesis; bone morphogenic protein; cell type; design; disability; loss of function; loss of function mutation; macrophage; monocyte; mouse model; mutant; novel; preclinical study; public health relevance; receptor; research study; stem

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 TGF�MP) in HHT1 or ALK1 (ACVLR1, a type 1 receptor of TGF�MP) 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（由申请人提供）：遗传性出血性毛细血管扩张症（HHT）中，多器官动静脉畸形（AVMs）和毛细血管扩张是引起复发性自发性出血的主要病理病变，可危及生命并导致长期残疾。一种流行的观点认为HHT是由单倍体不足引起的