Generation and Validation of Disease Models for Port-Wine Birthmarks

葡萄酒胎记疾病模型的生成和验证

• 批准号: 10727246
• 负责人: Wenbin Tan
• 金额: $ 19.67万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727246
• 关键词: Abnormal Cell; Address; Animal Model; Animals; Arteries; Arteriovenous malformation; Axon; Basement membrane; Blood Vessels; Blood capillaries; Cell Differentiation process; Cell model; Cells; Cerebrovascular system; Characteristics; Child; Clinical; Collagen Fiber; Congenital Abnormality; Data; Defect; Dermal; Dermis; Development; Diameter; Dilatation - action; Disease; Disease model; Endothelial Cells; Epigenetic Process; Epilepsy; Evaluation; Evolution; Exhibits; Face; Feasibility Studies; Fibroblasts; Generations; Hemangioma; Impairment; Implant; In Vitro; Intervention; Lasers; Length; Lesion; Live Birth; Modality; Modeling; Molecular; Molecular Profiling; Monitor; Morphology; Mus; National Institute of Arthritis, and Musculoskeletal, and Skin Diseases; Organoids; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pericytes; Phenotype; Physicians; Plug-in; Port-Wine Stain; Prevalence; Probability; Proliferating; Research; Scientist; Series; Severe Combined Immunodeficiency; Signal Pathway; Skin; Specific qualifier value; Stains; Strategic Planning; Sturge-Weber Syndrome; Symptoms; Technology; Therapeutic Studies; Validation; Vascularization; Veins; Xenograft procedure; clinical development; clinically relevant; effective therapy; endothelial stem cell; implantation; in vitro Model; in vivo; in vivo Model; in vivo evaluation; induced pluripotent stem cell; innovation; lymphatic vessel; malformation; model development; molecular phenotype; next generation sequencing; novel; skin lesion; stem cells; stem-like cell; subcutaneous; therapeutic development; therapy outcome; tool

Project Summary Vascular malformations (VMs) are resulted from developmental abnormalities in vasculatures including veins, arteries, capillaries, and lymphatic vessels. Treatment of VMs is a big challenge due to the large variety of lesion types, complexity of symptoms, and limited interventional options, which results in unsatisfied therapeutic outcomes. Port Wine Birthmarks (PWB) is one of the most common types of VMs. It mainly appears on the face and can be highly associated with Sturge Weber Syndrome (SWS) with brain blood vessels’ involvement and seizure disorders. One long-term obstacle to our understanding of the disease causes of PWB and the therapeutic development for it has been a lack of clinically relevant cell and animal models. In this proposal, we will take advantages of utilizing our current advancements in the generation of PWB-derived induced pluripotent stem cells (IPSCs) and their differentiated lineages such as endothelial cells (ECs) and vascular spheroids/organoids (VSs). VSs derived from PWB show larger diameters, longer lengths, and more tortuous branches as compared to the VSs derived from normal IPSCs. In addition, such vascular phenotypes can be reproduced in vivo after an implantation of spheroids/organoids into the mouse skin. These proof-of-principle and feasibility studies let us propose to develop in vitro and in vivo clinically relevant cell and organoid models derived from PWB patient’s IPSCs and validate them subsequently. For evaluation of in vitro cell and organoid models, we will perform a series of molecular and phenotypic characterizations of ECs and VSs derived from PWB IPSCs as compared to normal IPSCs. Furthermore, next generation sequencing approaches will be used to explore and integrate the molecular, epigenetic, and signaling pathway profiles that underlie the abnormal cell-fate and lineage-specification in PWB. These molecular pathological features will be further validated with PWB skin lesions. For evaluation of the in vivo model, we will implant VSs into skins in mice, monitor and characterize the dynamics of the vasculature formation and remodeling. We will determine the recapitulated PWB pathologies in this in vivo model as compared to the existing data from PWB skin lesions. The project is highly innovative as it aims to develop clinically relevant and paradigm-shift cell and organoid models for mechanistic and therapeutic studies of PWB. The use of patient-derived IPSCs, ECs, and VSs are unprecedented; the data is translational. These models are not only a significant evolution in disease model development for understanding of pathological characteristics of PWB, but also a substantial advancement in development of a novel platform for clinical therapeutic studies.

项目摘要血管畸形(VM)是由发育异常引起的 在血管系统中，包括静脉、动脉、毛细血管和淋巴管。对VM的处理是 由于病变类型繁多、症状复杂且有限，这是一个巨大的挑战 介入选择，导致治疗结果不满意。波尔图葡萄酒胎记 (PWB)是最常见的VM类型之一。它主要出现在面部，并可高度 伴发脑血管受累的斯特奇-韦伯综合征 癫痫发作障碍。阻碍我们了解PWB疾病原因的一个长期障碍 而其治疗进展一直缺乏临床相关的细胞和动物模型。 在这项提议中，我们将利用我们目前在这一代中的进步 PWB来源的诱导多能干细胞(IPSCs)及其分化的谱系，如 内皮细胞(ECs)和血管球体/器体(VSS)。源自PWB Show的VSS 与VSS派生的VSS相比，直径更大、长度更长、分支更弯曲 从普通的iPSCs。此外，这种血管表型可以在体内复制 将类球体/类器官植入小鼠皮肤。这些原则和可行性的证明 研究让我们建议建立体外和体内临床相关的细胞和有机模型。 从PWB患者的IPSCs中提取并随后验证。用于体外细胞的评估 和有机物模型，我们将执行一系列的分子和表型表征 与正常IPSCs相比，来自PWB IPSCs的ECS和VSS。此外，下一步 世代测序方法将用于探索和整合分子、表观遗传学、 和信号通路的特征，这些信号通路是异常细胞命运和谱系规范的基础 PWB。这些分子病理特征将在PWB皮肤损害中得到进一步验证。为 体内模型的评价，我们将VSS植入小鼠皮肤，监测和表征 血管形成和重塑的动力学。我们将确定概括的 本活体模型中的PWB病理与现有的PWB皮肤损伤数据进行了比较。 该项目具有很高的创新性，因为它的目标是开发具有临床相关性和范式转换的细胞和 用于pwb机制和治疗研究的有机体模型。使用患者派生的 IPSC、ECS和VSS是史无前例的；数据是可转换的。这些型号不仅是 疾病模型发展中对病理学理解的重大进展 PWB的特点，也是一种开发新平台的实质性进展 用于临床治疗研究。