Cutaneous Hemangiomas and Signal Transduction

描述（由申请人提供）：本申请侧重于机制 或发病机制或血管瘤和相关的血管生成。血管瘤是 最常见的皮肤血管病变的儿童，并存在于5 1岁婴儿的百分比。这些血管瘤可能生长到大尺寸 并且可能导致重要结构的压迫或高输出量心脏 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 高发病率，包括生长迟缓、感染和 不可逆性神经病变相当数量的血管瘤 治疗无效，导致死亡。 这些病变背后的信号转导通路并不完全是 明白血管瘤是一种反应性过程，与血管内的不平衡有关。 血管生成开关，导致宿主的增殖和迁移 内皮细胞对血管生成刺激的反应（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 以及它们在正常内皮细胞上的受体。主要研究者 开发了一种小鼠血管瘤模型，使用小鼠新生内皮细胞， 细胞系A9519。该模型概括了临床和组织学 人类血管瘤的特征。我们以前进行的研究 实验室已经显示单个信号转导途径激活， 磷酸肌醇-3-激酶，对于SYR中血管生成的调节至关重要 细胞，其通过连续的细胞培养从成年鼠内皮细胞中获得。 引入SV 40大T抗原和H-ras。我们认为， 丝裂原活化蛋白激酶（MAPK）和磷酸肌醇-3-激酶 （PI-3.-激酶）途径是小鼠良性血管瘤生长所必需的 还有人类这些途径的抑制提供了治疗的可能性， 血管瘤和其它皮肤血管生成疾病的治疗。 假设：MAPK和P1-3-激酶途径的激活是必需的， 体内血管瘤生长。 具体目标1。确定血管瘤中是否存在自分泌环 细胞在体外和体内。 具体目标2。为了确定MAPK和PI-3-激酶的激活在细胞凋亡中的作用， 使用显性负信号在小鼠血管瘤模型中的通路 转导基因和药理学抑制。 具体目标3。确定下游效应物的身份和功能 MAPK和PI 3-kinase在血管瘤中的表达。 本建议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，还从 本提案中描述的研究将导致更准确的诊断， 其它内皮肿瘤，如血管内皮瘤，卡波西肉瘤， 和血管肉瘤，以及导致新的治疗方法，以皮肤 疾病通过信号转导调节。

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.