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，目前尚无有效的治疗方法