PATHOPHYSIOLOGY OF CUTANEOUS VASCULAR LESIONS

这份职业发展奖提案关注的是老年痴呆症的发病机制 皮肤血管损伤。血管瘤是最常见的皮肤 儿童时期的血管病变，在10%的婴儿中存在 在1岁时。这些血管瘤可能会长得很大，结果 在重要结构受压，高输出量心衰，以及 凝血障碍。这种凝血障碍现象被称为卡萨巴赫- 梅里特综合征。大血管瘤的治疗需要长期的 使用类固醇或α-干扰素治疗，以及手术。一个重要的 这些血管瘤中有许多对治疗没有反应，导致 死亡。 对这些病变的病理生理学知之甚少，但初步了解 有证据表明，血管生成刺激因子和 抑制剂。我们已经建立了一种增生性血管的小鼠模型 通过序贯导入SV40大T抗原和 H-ras进入血管内皮细胞。此模式概括了临床和 非增殖性和增殖性鼻咽癌的组织学特征 血管瘤。我希望研究涉及到的信号转导途径 在上调血管生成刺激因子和下调血管生成因子方面 血管生成抑制剂。此外，我还发现， 内皮细胞表达血管内皮生长因子及其受体Flk-1，提示 一个可能的自分泌循环。最后，新型血管生成抑制剂 从一例自发性血管内皮瘤中分离出内皮抑素 细胞系。其作用机制尚不清楚。我希望能学到 内皮抑素介导的信号转导途径 血管生成抑制。血管生成自分泌环路的中断和 增殖中激活的信号转导通路的靶向性研究 血管病变可能为血管瘤提供新的治疗方法。 福克曼实验室在隔离和分离方面拥有丰富的经验 血管生成刺激物和抑制物的特征。按顺序 成为血管生成的独立研究员，精通 这些技术是必要的。开展研究的机会 并接受细胞生物学方面的正式培训， 蛋白质的提纯和鉴定，以及外科手术将 为申请人提供所需的培训 确立了他作为一名独立内科医生兼科学家的职业生涯。

This Career Development Award Proposal focuses on the pathogenesis of cutaneous vascular lesions. Hemangiomas are the most common cutaneous vascular lesions of childhood, and are present in 10 percent of infants at 1 year of age. These hemangiomas may grow to large size, resulting in compression of vital structures, high output cardiac failure, and coagulopathy. The coagulopathy phenomenon is known as the Kasabach- Merritt syndrome. Treatment of large hemangiomas requires lengthy treatment with steroids or alpha interferon, and surgery. A significant number of these hemangiomas do not respond to treatment, resulting in death. Little is known of the pathophysiology of these lesions, but preliminary evidence points to an imbalance of angiogenesis stimulators and inhibitors. We have developed a murine model of proliferative vascular lesions through the sequential introduction of SV40 large T antigen and H-ras into endothelial cells. This model recapitulates clinical and histologic features of both nonproliferative and proliferative hemangiomas. I wish to study the signal transduction pathways involved in upregulation of angiogenesis stimulators and downregulation of angiogenesis inhibitors. In addition, I have found that transformed endothelial cells express both VEGF and its receptor, flk-1, suggesting a possible autocrine loop. Finally, the novel angiogenesis inhibitor endostatin has been isolated from a spontaneous hemangioendothelioma cell line. Its mechanism of action is unknown. I hope to learn the signal transduction pathways through which endostatin mediates angiogenesis inhibition. Interruption of angiogenic autocrine loops and targeting of signal transduction pathways activated in proliferative vascular lesions may provide novel therapies for hemangiomas. The Folkman laboratory has extensive experience in the isolation and characterization of angiogenesis stimulators and inhibitors. In order to become an independent investigator in angiogenesis, proficiency in these techniques is necessary. The opportunity to carry out the studies outlined in this proposal and receive formal training in cell biology, protein purification and characterization, and surgical procedures will afford the applicant the training which is required toward the establishment of his career as an independent physician-scientist.