Lymphatic Vessel Abnormalities in CM-AVM

CM-AVM 中的淋巴管异常

• 批准号: 8884207
• 负责人: PHILIP D KING
• 金额: $ 39.72万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8884207
• 关键词: 1-Phosphatidylinositol 3-Kinase; Alleles; Arteriovenous malformation; Biopsy Specimen; Blood; Blood Vessels; Blood capillaries; Cells; Cessation of life; Chylothorax; Chylous Ascites; Cutaneous; Defect; Development; Disease; Drainage procedure; Embryonic Development; Event; Extravasation; Functional disorder; GTP-Binding Proteins; Gene Silencing; Genes; Genetic; Germ Lines; Goals; Growth Factor; Growth Factor Receptors; Human; Hyperplasia; Imaging technology; Inherited; Knowledge; Laboratories; Lead; Lesion; Life; Lymphatic Endothelial Cells; Lymphatic vessel; Lymphedema; Methods; Mission; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Genetics; Monomeric GTP-Binding Proteins; Morbidity - disease rate; Mus; Mutate; Mutation; Normalcy; Outcome; Pathogenesis; Patients; Pharmacotherapy; Protein Family; Public Health; Ras Signaling Pathway; Reporting; Research; Role; Sampling; Signal Transduction; Testing; Therapeutic Agents; United States National Institutes of Health; Vascular Diseases; Work; base; burden of illness; capillary; cell type; disability; genetic analysis; improved; innovation; malformation; mouse model; novel; progenitor; public health relevance; ras GTPase-Activating Proteins

 DESCRIPTION (provided by applicant): Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal dominant blood vascular disorder in humans that is caused by inherited inactivating mutations of the RASA1 gene. Lymphatic vessel (LV) abnormalities such as chylothorax, lymphedema and impaired LV drainage have also been reported in CM- AVM. RASA1 acts as a negative regulator of the Ras small GTPase during the course of growth factor receptor intracellular signal transduction. However, how RASA1 mutations lead to the development of LV abnormalities in CM-AVM is not well understood. A long-term goal of the King laboratory is to understand the role of the Ras signaling pathway in LV development and function. The overall objective of this application, which is consistent with this long-term goal, s to determine the cellular, molecular, and genetic basis of LV abnormalities in CM- AVM. Our central hypothesis is that LV abnormalities in CM-AVM arise as a consequence of deficient expression of RASA1 in LV valve cells and that dysregulated activation of specific Ras effectors in this cell type results in impaired valve development and function. Furthermore, we hypothesize that somatic inactivation of the wild type RASA1 allele at an early point in embryogenesis is necessary for the development of LV abnormalities in CM-AVM. The rationale for these studies is that they will inform as to the most effective means of drug therapy of LV abnormalities in CM-AVM and other diseases that are caused by hyper-activation of Ras. We propose to test the central hypothesis through the pursuit of three independent specific aims. In the first aim, we will use an inducible RASA1-deficient mouse model of LV abnormalities in CM-AVM to examine the influence of Rasa1 gene disruption upon LV valve development and function and its relationship to LV hyperplasia. In the second aim, we will use the same mouse model to examine which intracellular signaling cascades downstream of Ras drive the development of LV abnormalities in this disease. In the third aim, we will perform genetic analyses upon biopsy samples obtained from CM-AVM patients with LV abnormalities to identify which type(s) of somatic genetic events act in concert with the germline RASA1 mutation to give rise to LV lesions. The proposed studies are innovative because of the use of novel methods to assess LV valve function and mechanisms of RASA1 gene inactivation. The proposed studies are significant because they are expected to lead to a means of therapy for LV disease in CM-AVM. They are also expected to advance the field of LV research in general.

 描述(申请人提供)：毛细血管畸形-动静脉畸形(CM-AVM)是一种常染色体显性遗传的人类血管疾病，由RASA1基因的遗传失活突变引起。淋巴管(LV)异常，如乳糜胸、淋巴水肿和LV引流障碍也在CM-AVM中被报道。在生长因子受体胞内信号转导过程中，RASA1是Ras小GTP酶的负性调节因子。然而，RASA1突变如何导致CM-AVM中左室异常的发展还不是很清楚。King实验室的长期目标是了解RAS信号通路在LV发育和功能中的作用。本次应用的总体目标与S的这一长期目标一致，旨在确定CM-AVM中左室异常的细胞、分子和遗传学基础。我们的中心假设是，CM-AVM的左心室异常是由于左心室瓣膜细胞RASA1表达不足所致，这种细胞类型中特定RAS效应器的异常激活导致瓣膜发育和功能受损。此外，我们假设，在胚胎发育的早期，野生型RASA1等位基因的体细胞失活对于CM-AVM的LV异常的发展是必要的。这些研究的基本原理是，它们将为CM-AVM和其他由RAS过度激活引起的疾病提供最有效的药物治疗手段。我们建议通过追求三个独立的具体目标来检验中心假设。在第一个目的中，我们将使用可诱导的RASA1基因缺陷的小鼠CM-AVM左心室异常模型来检测RASA1基因突变对左心室瓣膜发育和功能的影响及其与左心室增生的关系。在第二个目标中，我们将使用相同的小鼠模型来检查RAS下游的哪些细胞内信号级联驱动这种疾病的左心室异常的发展。在第三个目标中，我们将对有左室异常的CM-AVM患者的活检样本进行基因分析，以确定哪种类型的体细胞遗传事件(S)与胚系RASA1突变一起导致左室病变。所提出的研究具有创新性，因为使用了新的方法来评估左心室瓣膜功能和RASA1基因失活的机制。这些拟议的研究具有重要意义，因为它们有望为CM-AVM中的LV疾病提供一种治疗手段。他们还有望在总体上推进LV研究领域。