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（由申请人提供）：毛细血管畸形-动静脉畸形（CM-AVM）是一种人类常染色体显性血管疾病，由 RASA1 基因的遗传失活突变引起，淋巴管（LV）异常，例如乳糜胸、淋巴水肿和淋巴管畸形。据报道，CM-AVM 中左心室引流受损，RASA1 在 Ras 小 GTP 酶过程中充当负调节因子。然而，RASA1 突变如何导致 CM-AVM 中 LV 异常的发生尚不清楚，King 实验室的长期目标是了解 Ras 信号通路在 LV 发生中的作用。本申请的总体目标与这一长期目标一致，即确定 CM-AVM 中 LV 异常的细胞、分子和遗传基础。 CM-AVM 的产生是由于 LV 瓣膜细胞中 RASA1 表达缺陷，并且该细胞类型中特定 Ras 效应子的失调激活导致瓣膜发育和功能受损。此外，我们一直在努力解决野生型 RASA1 等位基因的体细胞失活。在胚胎发生的早期阶段对于 CM-AVM 中左心室异常的发展是必要的。这些研究的基本原理是它们将提供治疗左心室异常的最有效方法。 CM-AVM 和由 Ras 过度激活引起的其他疾病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，我们将使用可诱导的 RASA1 缺陷小鼠模型。在 CM-AVM 中检查 Rasa1 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哪些细胞内信号级联下游。 Ras 驱动这种疾病中左心室异常的发展，我们将对从患有左心室异常的 CM-AVM 患者获得的活检样本进行遗传分析，以确定哪些类型的体细胞遗传事件与种系一致。 RASA1 突变引起左心室病变，因为使用了新方法来评估左心室瓣膜功能和 RASA1 基因失活机制，所以这项研究具有重要意义，因为它们有望找到一种治疗方法。 CM-AVM 中的左心室疾病也有望推动整个左心室研究领域的发展。