Determining the Mechanism for Pediatric Vascular Malformations: Investigation of Follicle Stimulating Hormone

确定小儿血管畸形的机制：卵泡刺激激素的研究

• 批准号: 9323475
• 负责人: Reid A. Maclellan
• 金额: $ 12.99万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-01-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9323475
• 关键词: ANGPT1 gene; Affect; Animal Model; Appearance; Back; Behavior; Biological Assay; Blood Vessels; Blood capillaries; Blood flow; Cell model; Cells; Cessation of life; Child; Childhood; Coculture Techniques; Communication; Complex; Congenital Abnormality; Data; Digestion; Disease; Endothelial Cells; Engineering; Excision; Exhibits; Fluorescence-Activated Cell Sorting; Follicle Stimulating Hormone; Follicle Stimulating Hormone Receptor; Functional disorder; GNAQ gene; Goals; Growth; Heart failure; Hemorrhage; Hormone Antagonists; Hormones; Human; Immunodeficient Mouse; Implant; Infection; Injectable; Investigation; Knock-in Mouse; Lesion; Life Cycle Stages; Lymphatic; Malignant Neoplasms; Measures; Methods; Modeling; Morbidity - disease rate; Morphogenesis; Mutation; Obstruction; Pain; Pathologic; Pathway interactions; Pericytes; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Population; Process; Production; Property; Puberty; Sclerotherapy; Stem cells; Structure; Suspensions; System; TEK gene; TdT-Mediated dUTP Nick End Labeling Assay; Testing; Therapeutic Embolization; Time; Tissue Engineering; Tissues; Tube; Umbilical vein; VEGFA gene; Vascular Diseases; Venous Malformation; Western Blotting; base; capillary; cell type; collagenase; density; experimental study; functional loss; improved; in vitro Assay; in vivo; inhibitor/antagonist; innovation; knockin animal; malformation; migration; mouse model; neovascularization; novel; operation; prevent; reconstruction; subcutaneous; targeted treatment; tissue repair

Project Summary Abstract The goal of this project is to understand the mechanism by which vascular malformations grow. 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 vascular malformations and other vascular diseases. Vascular malformations are common, affecting 1/200 children, and cause significant morbidity: disfigurement, obstruction, pain, infection, bleeding, heart failure, and death. Vascular malformations are particularly problematic because they are progressive and enlarge over time. Currently the mechanism for vascular malformations is unknown and there is no cure for these lesions. We propose the novel hypothesis that follicle-stimulating hormone (FSH) may be responsible for the progression of vascular malformations. The secretion of FSH mirrors the life cycle of these lesions (i.e., FSH surges during puberty when a vascular malformation is most likely to expand). Our preliminary data has shown that vascular malformations uniquely express 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 vascular malformations. Our first aim will isolate specific cell populations from vascular malformations to identify the cell type(s) that contain FSHR. Our second aim will test the effects of FSH on the angiogenic/vasculogenic properties of human-derived vascular malformation cells. Cell based assays will be used to determine whether FSH causes human vascular malformation endothelial cells, pericytes, or stem cells to exhibit a phenotype that promotes neovascularization. Finally, our third aim will test whether systemically administered FSH (or antagonists) affects the growth of vascular malformations in-vivo. Our validated murine models of lymphatic malformation and venous malformation and newly created in-vivo vascular malformation models will be used for these studies. The effects of FSH on the size, blood flow, and microvessel density on these lesions will be tested. These experiments will be high impact when we succeed in identifying the mechanism responsible for vascular malformations. For the first time we would be able to pursue a targeted approach for treating these lesions. For example, pathway specific topical, intralesional, and/or systemic FSH inhibitors could be developed to prevent the formation or growth of vascular malformations. Also, discoveries into the cause of these lesions 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).

项目摘要 这个项目的目标是了解血管畸形生长的机制。这将通知 我们了解血管形态发生的基本过程，重要的是，确定特定的途径， 可以开发哪些靶向疗法来改善受血管畸形影响的儿童的生活 和其他血管疾病。血管畸形是常见的，影响1/200的儿童， 显著发病率：毁容、梗阻、疼痛、感染、出血、心力衰竭和死亡。血管 畸形是特别成问题的，因为它们是渐进的并且随着时间的推移而扩大。目前 血管畸形的机制是未知的，并且没有治愈这些病变的方法。 我们提出了一个新的假设，即卵泡刺激素（FSH）可能是导致 血管畸形的进展。FSH的分泌反映了这些病变的生命周期（即，FSH 当血管畸形最有可能扩大时，青春期会激增）。我们的初步数据显示 血管畸形独特地表达FSH受体（FSHR），与其他正常和 病理性血管组织这些研究的目的是测试FSH（或其拮抗剂）是否影响 血管畸形的生长。我们的第一个目标是从血管畸形中分离出特定的细胞群 以鉴定含有FSHR的细胞类型。我们的第二个目标是测试FSH对 人源性血管畸形细胞的血管生成/血管生成特性。基于细胞的分析将是 用于确定FSH是否导致人血管畸形内皮细胞、周细胞或干细胞 表现出促进新生血管形成的表型。最后，我们的第三个目标将测试系统性地 施用的FSH（或拮抗剂）影响体内血管畸形的生长。我们经过验证的小鼠 淋巴管畸形和静脉畸形模型以及新创建的体内血管畸形 模型将用于这些研究。促卵泡激素对子宫内膜大小、血流量和微血管密度的影响 将对这些损伤进行测试。 当我们成功地确定了血管紧张素转换酶的机制时，这些实验将产生巨大的影响。 畸形这是我们第一次能够寻求一种有针对性的方法来治疗这些病变。为 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 血管畸形的形成或生长。同时，发现这些病变的原因将有助于我们 了解其他儿科血管病变的机制，并将提高我们的能力， 操纵其它系统中的新血管形成（例如，癌症、组织修复、工程学）。