Investigating the Role of Somatic Mutations in Arteriovenous Malformations

研究体细胞突变在动静脉畸形中的作用

基本信息

批准号：
10410345
负责人：
Daniel Snellings
金额：
$ 3.35万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2022-04-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10410345
关键词：
ACVRL1 gene Acute Affect Anemia Arteries Arteriovenous malformation Automobile Driving Belief Biological Biology Blood Blood Vessels Brain Brain Vascular Malformation Cell Culture Techniques Cells Cessation of life Chronic Clinical Clonal Expansion Collection Communities Data Development Disease Endothelial Cells Epistaxis Event Excision Fluorescent in Situ Hybridization Frequencies Future Gastrointestinal tract structure Gene Frequency General Population Genes Genetic Genetic Diseases Genotype Germ-Line Mutation Goals Growth Heart failure Hemorrhage Hereditary hemorrhagic telangiectasia Human Impairment Individual Inheritance Patterns Inherited KRAS2 gene Knock-out Lead Lesion Light Liver Liver Failure Lung MADH4 gene Manuscripts Medical Mendelian disorder Molecular Morbidity - disease rate Mosaicism Mucous Membrane Mutate Mutation Oncogenes Operative Surgical Procedures PIK3CA gene Pathogenesis Pathogenicity Pathway interactions Pericytes Pharmacologic Substance Phase Phenotype Play Poison Population Preparation Recurrence Research Resolution Role Shunt Device Signal Transduction Skin Skin Tissue Smooth Muscle Myocytes Somatic Mutation Source Stains Stroke Syndrome System Telangiectasis Testing Therapeutic Embolization Therapeutic Intervention Type I Epithelial Receptor Cell Veins Venous system Visceral Visualization Work base causal variant cell type cerebral cavernous malformations deep sequencing experimental study gene product insight loss of function loss of function mutation malformation mortality mouse model mutant novel transcriptome sequencing

项目摘要

PROJECT SUMMARY Hereditary Hemorrhagic Telangiectasia (HHT) is a Mendelian disease characterized by the development of multiple focal vascular malformations (VMs) including large visceral arteriovenous malformations in the brain, liver, and lungs; and numerous telangiectasia in mucosal and cutaneous tissue. These VMs are tortuous collections of vessels that result in the direct high-flow shunting of blood between arterial and venous systems. HHT-related VMs often lead to acute hemorrhage, chronic bleeding, anemia, stroke, heart and liver failure. Despite the morbidity and mortality associated with HHT, there remains no effective pharmaceutical therapy to treat HHT-related VMs; the only therapy is surgical embolization or resection. These surgical treatments do not treat the source of the disease and there are numerous cases of VM regrowth after surgical resection. In addition, these treatments are reserved for the largest VMs; however, individuals with HHT have a multitude of small VMs which frequently bleed and remain a significant, yet untreatable, medical problem. Decades of research have focused on understanding the underlying genetics and vascular biology of HHT-related VMs, however the molecular events that initiate VMs remain poorly understood. The overall objective of this proposal is to gain a fundamental understanding of the molecular events that initiate vascular malformation. We have long known that HHT is caused by autosomal dominant loss-of-function mutations in either ENG, ACVRL1, or SMAD4. These findings led to the belief that HHT-related VMs results from haploinsufficiency of the mutated gene; however, this mechanism does not account for why HHT-related VMs are strictly focal lesions despite the systemic mutation. Counter to the haploinsufficiency hypothesis, I have identified that HHT-related VMs harbor a somatic mutation in the same gene as the causal germline mutation resulting in biallelic loss-of-function of the gene product. These mutations are consistent with a Knudsonian two-hit mechanism, strongly supporting a functional role for somatic mutations in the pathogenesis of HHT-related VMs. The aims of this proposal build on this finding with the goal of understanding how these somatic mutations impair vascular development to result in vascular malformation. Successful completion of these specific aims will fill a long-standing critical gap in our understanding of HHT biology and may identify new molecules/pathways susceptible to therapeutic intervention. Aim 1: Identify the mutant cell type and determine the extent of mosaicism in the malformation. Aim 2: Elucidate the functional effects of the somatic mutation on mutant and wild-type cells. Aim 3: Interrogate the presence of somatic mutations in sporadic and hereditary brain VMs.

项目概要遗传性出血性毛细血管扩张症 (HHT) 是一种孟德尔疾病，其特征为多发性局灶性血管畸形（VM），包括大脑中的大内脏动静脉畸形，肝脏和肺；粘膜和皮肤组织内有大量毛细血管扩张。这些VM是曲折的导致动脉和静脉系统之间血液直接高流量分流的血管集合。 HHT 相关的 VM 常常导致急性出血、慢性出血、贫血、中风、心力衰竭和肝功能衰竭。尽管与 HHT 相关的发病率和死亡率很高，但仍然没有有效的药物治疗方法处理与 HHT 相关的虚拟机；唯一的治疗方法是手术栓塞或切除。这些手术治疗不治疗病源，手术切除后VM重新生长的病例很多。此外，这些处理是为最大的虚拟机保留的；然而，患有 HHT 的个体拥有大量小型虚拟机经常出血，仍然是一个严重但无法治疗的医疗问题。数十年的研究已经专注于了解 HHT 相关 VM 的基础遗传学和血管生物学，然而启动虚拟机的分子事件仍然知之甚少。该提案的总体目标是获得对引发血管畸形的分子事件的基本了解。我们早就知道 HHT 是由 ENG、ACVRL1 或 SMAD4 的常染色体显性功能丧失突变引起的。这些研究结果使人们相信，HHT 相关的 VM 是由突变基因的单倍体不足引起的；然而，这种机制并不能解释为什么 HHT 相关的 VM 是严格的局灶性病变，尽管存在全身性的损伤。突变。与单倍体不足假说相反，我发现与 HHT 相关的 VM 具有体细胞与致病种系突变相同的基因发生突变，导致该基因的双等位基因功能丧失产品。这些突变与努森两次打击机制一致，有力地支持了功能性体细胞突变在 HHT 相关 VM 发病机制中的作用。该提案的目标建立在这一发现的基础上目的是了解这些体细胞突变如何损害血管发育，从而导致血管畸形。成功完成这些具体目标将填补我们长期存在的关键空白了解 HHT 生物学，并可能识别易受治疗干预的新分子/途径。目标 1：鉴定突变细胞类型并确定畸形中嵌合的程度。目标 2：阐明体细胞突变对突变型和野生型细胞的功能影响。目标 3：探究散发性和遗传性脑 VM 中是否存在体细胞突变。