Cutaneous Hemangiomas and Signal Transduction

皮肤血管瘤和信号转导

• 批准号: 6649140
• 负责人: JACK L ARBISER
• 金额: $ 25.27万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6649140
• 关键词: angiogenesis; autocrine; biological signal transduction; cell line; enzyme activity; enzyme inhibitors; enzyme mechanism; hemangioma; human tissue; laboratory mouse; mitogen activated protein kinase; neoplastic transformation; pathologic process; phosphatidylinositol 3 kinase; skin circulation; tissue /cell culture; vascular endothelium

DESCRIPTION (provided by applicant): This application focuses on the mechanisms or pathogenesis or hemangiomas and associated angiogenesis. Hemangiomas are the most common cutaneous vascular lesions of childhood, and are present in 5 percent of infants at 1 year of age. These hemangiomas may grow to large sizes and may result in compression of vital structures or high output cardiac failure. Treatment of large hemangiomas requires lengthy treatment with steroids or alpha interferon, and surgery. These treatments are associated with a high level of morbidity, including growth retardation, infection, and irreversible neuropathy. A significant number of these hemangiomas do not respond to treatment, resulting in death. The signal transduction pathways that underlie these lesions are not completely understood. Hemangiomas are a reactive process associated with an imbalance in the angiogenic switch, resulting in the proliferation and migration of host endothelial cells to an angiogenic stimulus (host recruitment). This process may involve autocrine and paracrine loops between endothelial specific ligands and their receptors on normal endothelial cells. The principal investigator has developed a mouse model of hemangiomas, using the murine neonatal endothelial cell line A9519. This model recapitulates the clinical and histologic characteristics of human hemangiomas. Previous studies performed by our laboratory have shown that activation of a single signal transduction pathway, phosphoinositol-3-kinase, is critical for the regulation of angiogenesis in SYR cells, which are derived from adult murine endothelium through the sequential introduction of SV4O large T antigen and H-ras. We believe that activation of both the mitogen activated protein kinase (MAPK) and phosphoinositol-3-kinase (PI-3.-kinase) pathways are required for growth of benign hemangiomas in mice and humans. Inhibition of these pathways provides therapeutic possibilities for the treatment of hemangiomas and other cutaneous angiogenic disorders. Hypothesis: Activation of both MAPK and P1-3-kinase pathways is required for hemangioma growth in vivo. Specific Aim 1. To determine the presence of autocrine loops in hemangioma cells in vitro and in vivo. Specific Aim 2. To determine the role of activation of the MAPK and PI-3-kinase pathways in a murine model of hemangioma using dominant negative signal transduction genes and pharmacologic inhibition. Specific Aim 3. To determine the identity and function of downstream effectors of MAPK and PI3-kinase in hemangiomas. The studies outlined in this proposal will contribute to our basic understanding of cutaneous angiogenesis. In addition, insights gained from the studies described in this proposal will lead to more accurate diagnosis of other endothelial neoplasms, such as hemangioendothelioma, Kaposi's sarcoma, and angiosarcoma, as well as lead to novel therapeutic approaches to cutaneous disease through signal transduction modulation.

描述（申请人提供）：此申请重点介绍机制 或发病机理或血管瘤和相关的血管生成。血管瘤是 最常见的儿童皮肤血管病变，存在于5 1岁的婴儿的百分比。这些血管瘤可能长到大尺寸 并可能导致重要结构或高输出心脏的压缩 失败。大血管瘤的治疗需要长期治疗 类固醇或α干扰素和手术。这些治疗与 高水平的发病率，包括增长迟钝，感染和 不可逆的神经病。这些血管瘤中有大量没有 应对治疗，导致死亡。 这些病变构成的信号转导途径并非完全 理解。血管瘤是与失衡有关的反应性过程 血管生成开关，导致宿主的增殖和迁移 内皮细胞到血管生成刺激（宿主募集）。这个过程 可能涉及内皮特异性配体之间的自分泌和旁分泌环 及其受体在正常的内皮细胞上。首席调查员有 使用鼠新生儿内皮开发了血管瘤的小鼠模型 细胞系A9519。该模型概括了临床和组织学 人血管瘤的特征。以前的研究由我们进行 实验室表明，单个信号转导途径的激活， 磷酸肌醇-3-激酶对于调节SYR的血管生成至关重要 细胞通过顺序源自成年鼠内皮 引入SV4O大T抗原​​和H-Ras。我们相信激活 有丝分裂原活化蛋白激酶（MAPK）和磷酸肌醇-3-激酶 （pi-3.-激酶）小鼠良性血管瘤生长必需的途径 和人类。这些途径的抑制为治疗可能性 血管瘤和其他皮肤血管生成障碍的治疗。 假设：需要激活MAPK和P1-3-激酶途径 体内血管瘤生长。 具体目的1。确定血管瘤中自分泌环的存在 细胞体外和体内。 具体目的2。确定MAPK和PI-3-激酶激活的作用 使用显性阴性信号的血管瘤鼠模型中的途径 转导基因和药理抑制。 特定目标3。确定下游效应子的身份和功能 血管瘤中的MAPK和PI3-激酶。 该提案中概述的研究将有助于我们的基本 了解皮肤血管生成。此外，从中获得的见解 该提案中描述的研究将导致更准确的诊断 其他内皮肿瘤，例如血管内皮瘤，卡波西肉瘤， 和血管肉瘤，并导致皮肤新颖的治疗方法 通过信号转导调制疾病。