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.

血管畸形（VM）是由发育异常引起的 包括静脉、动脉、毛细血管和淋巴管在内的脉管系统中。VM的治疗是 由于病变类型多样，症状复杂， 介入选择，导致治疗结果不满意。波特酒商标 (PWB)是最常见的虚拟机类型之一。它主要出现在脸上，可以高度 与脑血管受累的Sturge Weber综合征（SWS）相关， 癫痫病一个长期的障碍，我们了解的疾病原因，PWB 并且其治疗发展一直缺乏临床相关的细胞和动物模型。 在这个建议中，我们将利用我们目前在这一代的进步， PWB衍生的诱导多能干细胞（IPSC）及其分化谱系， 内皮细胞（EC）和血管球状体/类器官（VS）。从PWB导出的VS显示 与导出的VS相比，直径更大、长度更长、分支更迂曲 正常的IPSC。此外，这种血管表型可以在体内复制后， 将球状体/类器官植入小鼠皮肤中。这些原理和可行性证明 研究使我们提出开发体外和体内临床相关的细胞和类器官模型 来自PWB患者的IPSC，并随后验证它们。用于体外细胞评价 和类器官模型，我们将进行一系列的分子和表型表征， 与正常IPSC相比，来自PWB IPSC的EC和VS。此外，接下来 代测序方法将用于探索和整合分子，表观遗传， 和信号传导途径的概况，其基础是异常的细胞命运和谱系规范， PWB。这些分子病理学特征将进一步验证PWB皮肤病变。为 为了评价体内模型，我们将VS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 与PWB皮肤病变的现有数据相比，该体内模型中的PWB病理。 该项目是高度创新的，因为它旨在开发临床相关和范式转变细胞， 类器官模型用于PWB的机制和治疗研究。使用患者源性 IPSC，EC和VS是前所未有的;数据是翻译的。这些模型不仅是 疾病模型开发中的重大进展， PWB的特性，而且在开发新平台方面也取得了实质性进展 用于临床治疗研究。