Determining the Mechanism for Infantile Hemangioma: Follicle-Stimulating Hormone

描述（由申请人提供）：本项目的目标是了解婴儿血管瘤（IH）生长的机制。这将告诉我们血管形态发生的基本过程，重要的是，确定可以开发靶向治疗的特定途径，以改善受IH和其他血管疾病影响的儿童的生活。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，并可引起显著的发病率：出血，溃疡，感染，重要结构的破坏（例如，鼻子、嘴唇）、视觉或呼吸阻塞、器官衰竭和死亡。目前，IH的机制尚不清楚，也没有治愈病变的方法。可能会给予药物以减缓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）是负责IH的机制。FSH的分泌正好反映了IH的生长周期，婴儿期FSH的升高与IH风险增加相关。我们的初步数据表明，IH独特地表达FSH受体（FSHR），与其他正常和病理性血管组织相反。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对人源性IH细胞的血管生成/血管生成特性的影响。将使用基于细胞的试验来确定FSH是否导致人IH内皮细胞（HemEC）、周细胞（HemPC）或干细胞（HemSC）表现出促进新血管形成的表型。我们的第二个目标是测试是否全身施用FSH（或拮抗剂）影响体内IH的生长。通过将皮下植入的人源IH干细胞（HemSC）植入免疫缺陷小鼠的背部，将创建经验证的IH鼠模型。将测试FSH对IH植入物的尺寸、血流量和微血管密度的影响。当我们成功地确定了IH的机制时，这些实验将产生很大的影响。这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的病态肿瘤。例如，可以开发途径特异性局部、病灶内和/或全身性FSH抑制剂来预防IH形成或生长。此外，对IH原因的发现将有助于我们了解其他儿科血管病变的机制，并将提高我们在其他系统中操纵新血管形成的能力（例如，癌症、组织修复、工程学）。

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).