Determining the Mechanism for Infantile Hemangioma: Follicle-Stimulating Hormone

确定婴儿血管瘤的机制：卵泡刺激激素

• 批准号: 8751873
• 负责人: Arin K. Greene
• 金额: $ 26.38万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8751873
• 关键词: 4 year old; Adrenal Cortex Hormones; Adrenal Glands; Affect; Age-Months; Angiopoietin-1; Animal Model; Appearance; Back; Behavior; Biological Assay; Birth; Blood Vessels; Blood flow; Bradycardia; Breathing; Cells; Cessation of life; Child; Childhood; Cicatrix; Coculture Techniques; Common Neoplasm; Communication; Complex; Congestive Heart Failure; Data; Deceleration; Deformity; Disease; Endothelial Cells; Engineering; Exhibits; Failure to Thrive; Female; Follicle Stimulating Hormone; Follicle Stimulating Hormone Receptor; Functional disorder; Goals; Growth; Hemorrhage; Hormone Antagonists; Hormones; Human; Hypoglycemia; Hypothyroidism; Immunodeficient Mouse; Implant; In Vitro; Infant; Infection; Injection of therapeutic agent; Intervention; Left; Lesion; Life Cycle Stages; Lip structure; Low Birth Weight Infant; Malignant Neoplasms; Measures; Modeling; Morbidity - disease rate; Morphogenesis; Mus; Nose; Organ failure; Pathogenesis; Pathway interactions; Pericytes; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Population; Process; Production; Proliferating; Property; Propranolol; Risk; Seizures; Skin; Stem cells; Strawberry nevus; Structure; System; Telangiectasis; Testing; Time; Timolol; Tissue Engineering; Tissues; Topical Corticosteroids; Tube; Ulcer; Vascular Diseases; Vascular Endothelial Growth Factor A; Vision; base; density; functional loss; girls; high risk; human stem cells; improved; in vivo; in vivo Model; infancy; inhibitor/antagonist; innovation; migration; neovascularization; novel; operation; prednisolone; prevent; public health relevance; research study; tissue repair; tumor; tumor growth

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).

这个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， 可以开发靶向治疗以改善IH儿童生活的途径， 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 出生后扩大，并可导致显著的发病率：出血，溃疡，感染，破坏重要的 结构（例如，鼻子、嘴唇）、视觉或呼吸阻塞、器官衰竭和死亡。目前，该机制 对于IH是未知的，并且没有治愈的病变。药物可能会被给予，试图减缓生长， IH，但这些药物与显著的发病率相关，其作用机制尚不清楚。 我们提出了新的假说，即卵泡刺激素（FSH）是负责的机制， IH. FSH的分泌正好反映了IH的生长周期，其在婴儿期的升高与 患IH的风险增加。我们的初步数据表明，IH独特地表达受体， FSH（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IH细胞的血管生成/血管生成特性。将使用基于细胞的测定来确定 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。我们的第二个目标将测试系统性地 给予的FSH（或拮抗剂）影响体内IH的生长。将建立经验证的IH鼠模型， 通过将人源性IH干细胞（HemSC）皮下植入小鼠背部， 免疫缺陷小鼠FSH对IH植入物大小、血流量和微血管密度的影响 会得到考验 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， 防止IH形成或生长。此外，对IH原因的发现将有助于我们了解其机制， 这是其他儿科血管病变的基础，并将提高我们操纵新生血管的能力， 其它系统（例如，癌症、组织修复、工程学）。