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（由申请方提供）：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RASA 1基因的遗传性失活突变引起。CM-AVM中还报告了淋巴管（LV）异常，如乳糜胸、水肿和LV引流受损。RASA 1在生长因子受体细胞内信号转导过程中作为Ras小GT酶的负调节剂。然而，RASA 1突变如何导致CM-AVM中LV异常的发展尚不清楚。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。本申请的总体目标与该长期目标一致，即确定CM- AVM中LV异常的细胞、分子和遗传基础。我们的中心假设是，CM-AVM中的LV异常是由于LV瓣膜细胞中RASA 1表达不足引起的，并且这种细胞类型中特定Ras效应物的激活失调导致瓣膜发育和功能受损。此外，我们假设，体细胞失活的野生型RASA 1等位基因在胚胎发生的早期点是必要的左心室畸形的发展CM-AVM。这些研究的基本原理是，它们将告知CM-AVM和其他由Ras过度激活引起的疾病中LV异常的最有效药物治疗方法。我们建议通过追求三个独立的具体目标来检验中心假设。在第一个目标中，我们将使用诱导型RASA 1缺陷小鼠模型的左心室畸形CM-AVM检查Rasa 1基因破坏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下游的细胞内信号级联驱动这种疾病中LV异常的发展。在第三个目标中，我们将对从患有LV异常的CM-AVM患者中获得的活检样本进行遗传分析，以确定哪种类型的体细胞遗传事件与生殖系RASA 1突变一致，从而引起LV病变。由于使用了新的方法来评估LV瓣膜功能和RASA 1基因失活机制，因此拟议的研究具有创新性。拟定的研究具有重要意义，因为它们有望为CM-AVM中的LV疾病提供一种治疗方法。他们还有望推动LV研究领域的整体发展。