Roles of Akt and immune regulation in the development of hemangiomas

描述（由申请人提供）： 本建议书描述了我作为一名医生科学家的学术生涯发展的研究培训计划。本杰明实验室在研究发育和肿瘤发生中血管生成的调节方面具有丰富的经验，并开发了独特的工具来研究体内内皮细胞中的信号转导。有机会进行本提案中概述的研究将为我成为一名独立的医生科学家提供必要的培训。我的研究目标是了解皮肤血管病变的发病机制。血管瘤是婴儿期最常见的软组织肿瘤，发生在5%至10%的白人婴儿中。尽管 这些血管肿瘤可能导致的频率和功能和身体损害，对其发病机制知之甚少。在支持这一建议，我有初步的数据，暗示了一个重要的作用，Akt在血管瘤的形成，并建立了一个新的小鼠模型血管瘤的诱导和内皮细胞特异性表达的组成性活性myristylated Akt（myrAkt）。此外，当杂交到免疫缺陷的无胸腺nu/nu背景中时，myrAkt转基因小鼠响应于过度活化的Akt而产生广泛的血管瘤。这些发现暗示了免疫调节在该模型中血管瘤形成中的作用。我假设内皮细胞中持续的Akt激活足以促进血管瘤的发展，并且血管瘤的形成受到免疫系统的调节。我将测试这些假设，作为我长期目标的第一步，为患有毁容或危及生命的血管瘤的儿童设计治疗方案。我的目的是确定（1）Akt及其下游效应子mTOR的缺失是否抑制血管瘤的形成;（2）通过PTEN的缺失激活Akt是否足以形成血管瘤;（3）T细胞在血管瘤发展中的免疫调节作用。拟议的研究将增加我们对内皮细胞行为如何调节的理解，并帮助我们更好地了解其他血管肿瘤，如血管内皮瘤和血管肉瘤，并通过信号转导调节在血管肿瘤的治疗中开辟新的治疗选择。 (End摘要）

DESCRIPTION (provided by applicant): This proposal describes my research training program for the development of an academic career as a physician scientist. The Benjamin laboratory has extensive experience in studying the regulation of angiogenesis in development and tumorigenesis, and has developed unique tools to study signal transduction in endothelial cells in vivo. The opportunity to carry out the studies outlined in this proposal will provide the training necessary for me to become an independent physician scientist. My research goal is to understand the pathogenesis of cutaneous vascular lesions. Hemangiomas are the most common soft-tissue tumor of infancy, occurring in 5 to 10 percent of Caucasian infants. Despite the frequency and functional and physical impairment these vascular tumors can cause, little is known about their pathogenesis. In support of this proposal, I have preliminary data that implicate an important role of Akt in hemangioma formation, and have established a novel mouse model of hemangioma in response to inducible and endothelial cell-specific expression of constitutively active myristylated Akt (myrAkt). Furthermore, when crossed into immunodeficient athymic nu/nu background, myrAkt transgenic mice develop widespread hemangiomas in response to hyperactivated Akt. These findings implicate the role of immune regulation in hemangioma formation in this model. I hypothesize that sustained Akt activation in endothelial cells is sufficient for the development of hemangioma, and that hemangioma formation is modulated by the immune system. I will test these hypotheses as a first step in my long-term goal of designing therapy for children with disfiguring or life-threatening hemangiomas. My aims are to determine (1) whether loss of Akt and its downstream effector mTOR inhibits hemangioma formation; (2) whether activation of Akt through loss of PTEN is sufficient to form hemangioma; and (3) the role of immune regulation by T cells in the development of hemangiomas. The proposed studies will increase our understanding of how endothelial cell behavior is regulated, and help us better understand other vascular neoplasms, such as hemangioendothelioma and angiosarcoma, and open new therapeutic options in the treatment of vascular tumors through signal transduction modulation. (End of Abstract)