Systemic sclerosis (SSc) vasculopathy: Improved clinical monitoring and treatment

系统性硬化症(SSC；硬皮病)是一种复杂的自身免疫性疾病，没有治愈或有效的方法 对疾病的许多破坏性方面的治疗。小鼠模型不能概括SSC的所有特征， 授权进行人体研究以了解这种复杂的发病机制。中位生存期约11年。 SSC诊断和与SSC相关的国家医院费用估计每年超过2.75亿美元。SSC影响250人 在美国每100万人中，退伍军人健康管理局的患病率要高出约3-4倍 病人。SSC的发病机制以免疫异常、血管改变为特征，尤其是在 胃肠道微血管形成和纤维化，但这些机制的因果关系 胃肠道(GIT)是SSc中最常见的皮外器官损害系统，目前尚不清楚。 我们之前的工作由I01 CX002111-01《系统性硬化症(SSC)血管病变：改进》支持 《临床监测与治疗》发现，无论是大动脉(即肱动脉)，还是大动脉 微血管(即小动脉和毛细血管)内皮功能障碍是SSC的一个重要特征。功能失调 内皮导致血管通透性增加，组织免疫细胞浸润增加，血管生成迟钝 容量、血管反应性和组织血流量受损。虽然我们敏锐地证明了这一点，但我们可以提高 这种血管功能障碍、临床干预受到试验设计问题的限制，并通过以下方式得到极大改善 专门研究疾病机制的模型。我们发现了一种新的量化方法 口腔微血管改变(舌下视频显微镜)与SSc的GIT症状相关。 这个舌下视频显微镜测量的是维持血管系统动态平衡的糖萼， 包括控制血管通透性和微血管张力，防止微血管血栓形成，以及 调节白细胞黏附。 在我们提出的研究的第一个具体目标中，我们将对糖萼进行自然历史研究， 它与胃肠道疾病患者报告结果(PRO)和包括指端溃疡在内的终末期血管病变特征的关系 高血压(DU)、肺动脉高压(PH)、硬皮病肾危象(SRC)、钙质沉着症和毛细血管扩张症。在第二个 我们将开发一种新的模型来进一步研究这些终末期血管病变 患有SSc的退伍军人的特征(DU、PH、SRC、钙质沉着症、毛细血管扩张症和严重的GIT症状)。我们会 从他们的血液和年龄中产生的可诱导多潜能干细胞(IPSC)产生内皮细胞(EC)- 频率和性别与健康对照组相匹配。该项目的主要研究目标是在我们的 目前针对患有自发性硬化症的退伍军人的临床研究计划已经确定了自发性硬化症的重要体内方面 血管病变及其与PRO的关系。此项目更新的总体目标是定义SSC-GIT 通过口腔血管系统中的一系列微血管测量来检测血管病变，并将其与 症状，终末期血管病变的临床特征，和糖萼特征。然后我们将调查 通过建立SSC-IPSC-EC模型研究终末期血管并发症的病因学 测试渗透性、愈合和白细胞滚动。因此，这项建议将澄清SSc血管病变 通过一系列舌下微血管显微镜，GIT PRO，糖肾功能障碍的标志物， 以及检测外周血中产生的SSC-IPSC-EC。这种血管病变的特征可能 使我们能够确定有针对性的临床评估，制定有效的管理计划，并应用治疗 筛查这种影响退伍军人生活质量的毁灭性疾病，目前我们有 对发病机制的了解非常有限。重要的是，在这个项目中开发的新的IPSC模型具有 有可能用于其他罕见疾病，其特点是影响退伍军人的血管功能障碍。

Systemic sclerosis (SSc; scleroderma) is a complex autoimmune disease without a cure or an effective therapy for the many devastating aspects of disease. Mouse models do not recapitulate all features of SSc, mandating human studies for understanding this complex pathogenesis. The median survival is ~11 years after SSc diagnosis and the estimated national hospital costs related to SSc exceed 275 million yearly. SSc affects 250 per 1 million people in the US, with a ~3-4 time greater prevalence among Veteran’s Health Administration patients. The pathogenesis of SSc is characterized by immunological abnormalities, vascular changes, notably in the microvasculature, and fibrosis, yet both the cause and effect of these mechanisms within the gastrointestinal tract (GIT), which is the most common extra-cutaneous organ system damaged in SSc, is unknown. Our previous work supported by I01 CX002111-01 “Systemic sclerosis (SSc) vasculopathy: Improved clinical monitoring and treatment” discovered that that both large artery (i.e., brachial artery), as well as microvascular (i.e., arterioles and capillaries) endothelial dysfunction is a critical feature of SSc. A dysfunctional endothelium leads to increased vascular permeability, greater tissue immune cell infiltration, blunted angiogenic capacity and impaired vascular reactivity and tissue blood flow. While we showed that acutely we could improve this vascular dysfunction, clinical interventions are limited by trial design issues and are greatly improved by models that specifically study the mechanism of disease. We identified a novel method for quantifying microvascular change in the oral cavity (sublingual videomicroscopy) that correlates to GIT symptoms in SSc. This sublingual videomicroscope measures the glycocalyx, which maintains homeostasis of the vasculature, including controlling vascular permeability and microvascular tone, preventing microvascular thrombosis, and regulating leukocyte adhesion. In the first specific aim of our proposed study, we will perform a natural history study of the glycocalyx, its relation to GIT patient reported outcomes (PRO) and end-stage vasculopathy features, including digital ulcers (DU), pulmonary hypertension (PH), scleroderma renal crisis (SRC), calcinosis, and telangiectases. In the second specific aim of the proposed study, we will develop a novel model to further study these end-stage vasculopathy features (DU, PH, SRC, calcinosis, telangiectases, and severe GIT symptoms) in Veterans with SSc. We will generate endothelial cells (EC) from inducible pluripotential stem cells (iPSC) created from their blood and age- frequency and sex matched healthy controls. The main research objective of this project is to build upon our current clinical research program for our Veterans with SSc that has identified important in vivo aspects of SSc vasculopathy and its relation to PRO. The over-arching goal of this project renewal is to define SSc-GIT vasculopathy through serial microvascular measurements in the vasculature of the mouth and correlate these to symptoms, end-stage vasculopathy clinical features, and glycocalyx characterization. We will then investigate the etiology of end-stage vascular complications through the establishment of a SSc-iPSC-EC model that can be tested for permeability, healing, and leukocyte rolling. Thus, this proposal will clarify SSc vasculopathy pathogenesis through serial sublingual microvascular microscopy, GIT PRO, markers of glycocalyx dysfunction, and testing of SSc-iPSC-EC generated from peripheral blood. This vasculopathy characterization can potentially allow us to identify targeted clinical assessments, develop effective management plans, and apply therapeutic screens for this devastating disease that effects our Veterans quality of life, and for which we currently have a very limited understanding of pathogenesis. Importantly, the novel iPSC model developed in this project has the potential to be used in other rare diseases characterized by vascular dysfunction that effect our Veterans.