Determining the Mechanism for Infantile Hemangioma: Follicle-Stimulating Hormone

这个项目的目标是了解婴儿血管瘤(IH)生长的机制。这将是 告诉我们血管形态发生的基本过程，重要的是，识别特定的 可为其开发有针对性的治疗以改善受IH和 其他血管疾病。IH是儿童最常见的肿瘤，影响2%-5%的婴儿。它迅速地 出生后肿大，可导致严重的发病率：出血、溃疡、感染、重要的 结构(如鼻子、嘴唇)、视力障碍或呼吸障碍、器官衰竭和死亡。目前的机制是 对于IH，目前还不清楚，这种病变也没有治愈方法。给药可能是为了减缓肿瘤的生长。 但这些药物与显著的发病率有关，其作用机制尚不清楚。 我们提出了一个新的假设，即卵泡刺激素(FSH)负责的机制是 啊。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 罹患IH的风险增加。我们的初步数据显示，IH独特地表达了 FSH(FSHR)，与其他正常和病理血管组织不同。这些研究的目标是测试 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卵泡刺激素对 人源性IH细胞的血管生成/血管生成特性。将使用基于细胞的分析来确定 促性腺激素是否会导致人IH内皮细胞(HemECs)、周细胞(HemPC)或干细胞(HemSCs) 表现出促进新生血管形成的表型。我们的第二个目标将测试系统地 体内应用FSH(或拮抗剂)影响IH的生长。一种经过验证的IH小鼠模型将是 通过将人类来源的IH干细胞(HemSCs)植入人体背部的皮下 免疫缺陷小鼠。促卵泡激素对IH种植体大小、血流量和微血管密度的影响 将会受到考验。 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，特定途径的局部、局部和/或全身FSH抑制剂可以开发成 防止间质纤维化的形成或生长。此外，对高血压病因的发现将有助于我们理解高血压的机制 这是其他儿科血管病变的基础，并将提高我们处理新生血管的能力 其他系统(如癌症、组织修复、工程学)。

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).