Determining the Mechanism for Infantile Hemangioma: Follicle-Stimulating Hormone

描述(由申请者提供)：这个项目的目标是了解婴儿血管瘤(IH)生长的机制。这将使我们了解血管形态发生的基本过程，重要的是，确定可以开发有针对性的治疗以改善受IH和其他血管疾病影响的儿童的具体途径。IH是儿童最常见的肿瘤，影响2%-5%的婴儿。它在出生后迅速扩大，可能导致严重的发病率：出血、溃疡、感染、重要结构(如鼻子、嘴唇)的破坏、视力或呼吸障碍、器官衰竭和死亡。目前，IH的发病机制尚不清楚，目前尚无治愈方法。可能会给出药物以减缓IH的生长，但这些药物与显著的发病率相关，其作用机制尚不清楚。我们提出了一个新的假说，即卵泡刺激素(FSH)参与了IH的发病机制。FSH的分泌准确地反映了IH的生长周期，其在婴儿期的升高与IH的风险增加相关。我们的初步数据表明，与其他正常和病理血管组织相比，IH独特地表达FSH受体(FSHR)。这些研究的目的是测试FSH(或其拮抗剂)是否影响IH的生长。我们的第一个目标是测试FSH对人来源的IH细胞血管生成/血管生成特性的影响。基于细胞的分析将被用来确定FSH是否会导致人类IH内皮细胞(HemECs)、周细胞(HemPC)或干细胞(HemSCs)表现出促进新生血管的表型。我们的第二个目标是测试全身应用FSH(或拮抗剂)是否影响体内IH的生长。通过将植入免疫缺陷小鼠背部皮下的人源性IH干细胞(HemSCs)，将创建一种经过验证的IH小鼠模型。FSH对IH植入物的大小、血流量和微血管密度的影响将被测试。这些实验将在我们成功确定IH的机制时产生重大影响。这将是我们第一次能够寻求一种有针对性的方法来治疗这种常见和病态的肿瘤。例如，可以开发特定途径的局部、局部和/或全身FSH抑制剂来防止IH的形成或生长。此外，对IH病因的发现将帮助我们了解其他儿科血管病变背后的机制，并将提高我们在其他系统(如癌症、组织修复、工程学)中操纵新生血管的能力。

DESCRIPTION (provided by applicant): The goal of this project is to understand the mechanism by which infantile hemangioma (IH) grows. This will inform us about the fundamental process of vascular morphogenesis and, importantly, identify specific pathways for which targeted therapies can be developed to improve the lives of children affected by IH and other vascular diseases. IH is the most common tumor of childhood, affecting 2-5% of infants. It rapidly enlarges after birth and can cause significant morbidity: bleeding, ulceration, infection, destruction of important structures (e.g., nose, lips), blockage of vision or breathing, organ failure, and death. Currently the mechanism for IH is unknown and there is no cure for the lesion. Drugs may be given in an attempt to slow the growth of IH, but these medications are associated with significant morbidity and their mechanism of action is unknown. We propose the novel hypothesis that follicle-stimulating hormone (FSH) is responsible for the mechanism of IH. The secretion of the FSH exactly mirrors the growth cycle of IH, and its elevation in infancy correlates with an increased risk of having IH. Our preliminary data has shown that IH uniquely expresses the receptor for FSH (FSHR), in contrast to other normal and pathological vascular tissues. The goal of these studies is to test whether FSH (or its antagonists) affects the growth of IH. Our first aim will test the effects of FSH on the angiogenic/vasculogenic properties of human-derived IH cells. Cell based assays will be used to determine whether FSH causes human IH endothelial cells (HemECs), pericytes (HemPCs), or stem cells (HemSCs) to exhibit a phenotype that promotes neovascularization. Our second aim will test whether systemically administered FSH (or antagonists) affects the growth of IH in vivo. A validated murine model of IH will be created by implanting human-derived IH stem cells (HemSCs) placed subcutaneously into the backs of immunodeficient mice. The effects of FSH on the size, blood flow, and microvessel density on the IH implants will be tested. These experiments would be high impact when we succeed in identifying the mechanism responsible for IH. For the first time we would be able to pursue a targeted approach for treating this common and morbid tumor. For example, pathway specific topical, intralesional, and/or systemic FSH inhibitors could be developed to prevent IH formation or growth. Also, discoveries into the cause of IH will help us understand the mechanisms that underlie other pediatric vascular lesions, and will improve our ability to manipulate neovascularization in other systems (e.g., cancer, tissue repair, engineering).