Roles of Akt and immune regulation in the development of hemangiomas

描述(由申请人提供)： 这份提案描述了我为发展作为内科科学家的学术生涯而进行的研究培训计划。本杰明实验室在研究血管生成在发育和肿瘤发生中的调控方面拥有丰富的经验，并开发了独特的工具来研究体内内皮细胞的信号转导。有机会开展这项提议中概述的研究，将为我成为一名独立的内科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。血管瘤是最常见的婴儿软组织肿瘤，发生在5%至10%的高加索婴儿中。尽管 这些血管肿瘤可能导致的频率和功能和身体损害，其发病机制知之甚少。为了支持这一建议，我有初步的数据表明Akt在血管瘤的形成中扮演着重要的角色，并建立了一种新的血管瘤小鼠模型，以响应可诱导的和内皮细胞特异性表达的成分活性的Myristylated Akt(MyrAkt)。此外，当进入免疫缺陷的无性系nu/nu背景时，myrAkt转基因小鼠会发生广泛的血管瘤，以响应Akt的过度激活。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。我推测，内皮细胞持续的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。我将检验这些假设，作为我为患有毁容或危及生命的血管瘤的儿童设计治疗方案的长期目标的第一步。我的目标是确定(1)Akt及其下游效应因子mTOR的缺失是否抑制了血管瘤的形成；(2)通过PTEN的缺失激活Akt是否足以形成血管瘤；(3)T细胞在血管瘤发生发展中的免疫调节作用。这些研究将增加我们对血管内皮细胞行为调控的理解，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为血管肿瘤的治疗开辟新的治疗选择。 (摘要结束)

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)