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.

全身性硬皮病（SSC;硬皮病）是一种复杂的自身免疫疾病，没有治愈或有效 疾病许多毁灭性方面的治疗。鼠标模型不会概括SSC的所有功能， 要求人类研究以理解这种复杂的发病机理。中位生存时间约11年 SSC诊断和估计与SSC有关的国家医院费用每年超过2.75亿。 SSC影响250 美国每100万人，在退伍军人卫生管理中，患病率更高3-4次 患者。 SSC的发病机理的特征是免疫异常，血管变化，特别是在 微脉管系统和纤维化，但这些机制在胃肠道中的原因和作用既是 道（git）是SSC中最常见的二骨外器官系统，这是未知的。 我们以前由I01 CX002111-01支持的工作“系统性硬化症（SSC）血管病：改进 临床监测和治疗”发现，大动脉（即肱动脉）以及 微血管（即动脉和毛细血管）内皮功能障碍是SSC的关键特征。功能失调 内皮导致血管渗透性增加，组织免疫球体浸润较大，血管生成性钝化 容量和血管反应性和组织血流受损。虽然我们表明我们可以改善 这种血管功能障碍，临床干预措施受试验设计问题的限制，并大大改善 专门研究疾病机制的模型。我们确定了一种量化的新方法 口腔中的微血管变化（舌下视频显微镜）与SSC中的GIT符号相关。 这种舌下视频显微镜测量了维持脉管系统稳态的糖囊肿 包括控制血管通透性和微血管张力，防止微血管血栓形成和 调节白细胞粘附。 在我们提出的研究的第一个具体目的中，我们将对糖蛋白的自然史研究， 它与GIT患者报告的结果（PRO）和终阶段的血管病特征的关系，包括数字溃疡 （DU），肺动脉高压（pH），硬皮病肾脏危机（SRC），钙化病和尾血管酶。在第二个 拟议研究的具体目的，我们将开发一个新型模型，以进一步研究这些终阶段的血管病 具有SSC的退伍军人中的特征（DU，pH，SRC，钙化症，尾te骨和严重的GIT符号）。我们将 由诱导多依次干细胞（IPSC）产生内皮细胞（EC），由其血液和年龄产生 频率和性别匹配的健康对照。该项目的主要研究目标是在我们的 当前针对SSC退伍军人的临床研究计划已确定了SSC的重要体内方面 Vasculopathy及其与Pro的关系。该项目更新的整个目标是定义SSC-GIT 通过嘴巴的串行微血管测量的血管病变，将其与这些测量 症状，终末期血管病临床特征和糖脂表征。然后，我们将调查 通过建立SSC-IPSC-EC模型的终阶段血管并发症的病因 测试了渗透性，愈合和白细胞滚动。那就是该建议将澄清SSC VasculoPathy 通过连续舌下微血管显微镜，Git Pro，糖脂功能障碍的标记的发病机理， 以及由外周血产生的SSC-IPSC-EC测试。这种血管病的特征可能会可能 允许我们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 这种毁灭性疾病的屏幕影响我们的退伍军人生活质量，我们目前有一个 对发病机理的理解非常有限。重要的是，该项目中开发的新型IPSC模型具有 潜在用于其他稀有疾病，其特征是影响我们退伍军人的血管功能障碍。