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

系统性硬化症 (SSc) 血管病：改进临床监测和治疗

• 批准号: 10252115
• 负责人: Tracy Minan Frech
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10252115
• 关键词: Acute; Address; Adhesions; Affect; Age; Animal Model; Apoptosis; Apoptotic; Arteries; Autoantibodies; Autoimmune Diseases; Biopsy; Blood; Blood Vessels; Blood capillaries; Blood flow; Calcinosis; Cell Line; Cell model; Cells; Clinical; Clinical Research; Clinical assessments; Clinical effectiveness; Complex; Complication; Cultured Cells; Cutaneous sclerosis; Data; Dermal; Development; Diagnosis; Diffuse; Digestive System Disorders; Disease; Endothelial Cells; Endothelium; Etiology; Fibroblasts; Fibrosis; Frequencies; Functional disorder; Gastrointestinal tract structure; Glycocalyx; Goals; Health; Homeostasis; Hospital Costs; Human; Immune; Immunologics; Impairment; In Vitro; Infiltration; Intervention; Kidney; Leukocyte Rolling; Leukocytes; Malnutrition; Measurement; Measures; Methods; Microscopic; Microscopy; Microvascular Dysfunction; Military Personnel; Modeling; Monitor; Morbidity - disease rate; Natural History; Oral cavity; Organ; Oxidative Stress; Pathogenesis; Patient Outcomes Assessments; Patients; Permeability; Phenotype; Predictive Value; Prevalence; Prognosis; Pulmonary Hypertension; Quality of life; Rare Diseases; Research; Scleroderma; Signal Transduction; Skin; Symptoms; Systemic Scleroderma; Systemic disease; Testing; Therapeutic; Therapeutic Studies; Thick; Thrombosis; Time; Tissues; Ulcer; Vascular Diseases; Vascular Permeabilities; Veterans; Veterans Health Administration; Video Microscopy; Visit; Work; arteriole; base; body system; brachial artery; clinical practice; density; digital; disease mechanisms study; effective therapy; endothelial dysfunction; endothelial stem cell; evidence base; healing; health assessment; improved; in vitro testing; in vivo; induced pluripotent stem cell; insight; mortality; mouse model; novel; peripheral blood; prevent; programs; sex; stem cell model; stem cells; symptomatology; targeted treatment; therapeutic evaluation; tool; trial design; wound healing

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.

系统性硬化症（SSc；硬皮病）是一种复杂的自身免疫性疾病，无法治愈或有效 针对疾病许多破坏性方面的治疗方法并不能概括 SSc 的所有特征， 需要进行人体研究来了解这种复杂的发病机制，中位生存期约为 11 年。 SSc 诊断和估计与 SSc 相关的全国医院费用每年超过 2.75 亿 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高出约 3-4 倍 SSc 的发病机制以免疫异常、血管变化为特征，尤其是在患者中。 微血管系统和纤维化，以及胃肠道内这些机制的原因和影响 肠道 (GIT) 是 SSc 中最常见受损的皮外器官系统，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：改善 临床监测和治疗”发现，大动脉（即肱动脉）以及 微血管（即小动脉和毛细血管）内皮功能障碍是 SSc A 功能障碍的一个关键特征。 内皮导致血管通透性增加、组织免疫细胞浸润增加、血管生成减弱 虽然我们表明我们可以迅速改善。 对于这种血管功能障碍，临床干预受到试验设计问题的限制，并且可以通过以下方法得到极大改善： 我们确定了一种专门研究疾病机制的模型。 口腔微血管变化（舌下视频显微镜）与 SSc 的胃肠道症状相关。 这种舌下视频显微镜可测量糖萼，它维持脉管系统的稳态， 包括控制血管通透性和微血管张力，预防微血管血栓形成，以及 调节白细胞粘附。 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， 其与 GIT 患者报告结果 (PRO) 和终末期血管病变特征（包括指溃疡）的关系 （DU）、肺动脉高压（PH）、硬皮病肾危象（SRC）、钙质沉着和毛细血管扩张。 根据拟议研究的具体目标，我们将开发一种新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、毛细血管扩张和严重胃肠道症状）。 从其血液和年龄产生的诱导性多能干细胞（iPSC）中产生内皮细胞（EC） 该项目的主要研究目标是建立在我们的频率和性别匹配的健康对照的基础上。 当前针对患有 SSc 的退伍军人的临床研究计划已确定了 SSc 的重要体内方面 血管病变及其与 PRO 的关系 该项目更新的总体目标是定义 SSc-GIT。 通过口腔血管系统的连续微血管测量来确定血管病变，并将这些与 然后我们将研究症状、终末期血管病变的临床特征和糖萼特征。 通过建立 SSc-iPSC-EC 模型来研究终末期血管并发症的病因 测试渗透性、愈合和白细胞滚动因此，该提案将阐明 SSc 血管病变。 通过系列舌下微血管显微镜、GIT PRO、糖萼功能障碍标记物了解发病机制， 以及对从外周血中产生的 SSc-iPSC-EC 进行测试，这种血管病变特征可能是潜在的。 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，我们目前有针对这种疾病的筛查 对发病机制的了解非常有限。重要的是，该项目开发的新型 iPSC 模型具有以下特点： 有潜力用于治疗影响我们退伍军人的以血管功能障碍为特征的其他罕见疾病。