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: 9285707
• 负责人: Tracy Minan Frech
• 金额: $ 17.59万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9285707
• 关键词: Adopted; Antioxidants; Autoimmune Diseases; Biological Markers; Biopsy; Blood Vessels; Caliber; Cicatrix; Clinic Visits; Clinical; Consent; Data; Development; Disease; Double-Blind Method; Early Diagnosis; Enzymes; Event; FDA approved; Fibrosis; Functional disorder; Impairment; Intervention; Link; Longitudinal Studies; Measures; Mediating; Molecular; Monitor; NADPH Oxidase; Oral; Outcome; Oxidants; Oxidative Stress; Pathogenicity; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Predictive Value; Process; Randomized; Reporting; Risk; Scientist; Scleroderma; Skin; Solid; Systemic Scleroderma; Techniques; Testing; Therapeutic; Ulcer; Vascular Diseases; antioxidant enzyme; arteriole; base; brachial artery; collaborative approach; design; digital; experience; improved; improved outcome; insight; novel; public health relevance; reactive hyperemia; response; skills; tetrahydrobiopterin; vascular endothelial dysfunction

 DESCRIPTION (provided by applicant): Systemic sclerosis (SSc; scleroderma) is a complicated autoimmune disease characterized by blood vessel change (vasculopathy) and scarring (fibrosis). SSc is a disease in which the blood vessel changes precede fibrosis. Most importantly, early diagnosis may result in improved outcomes for SSc patients. Our pilot data using flow-mediated dilation (FMD), a noninvasive, objectively measured parameter, suggests that compared to healthy controls, SSc patients had significantly smaller brachial artery diameter, and blunted peripheral vascular reactivity and endothelial function. SSc patients with digital ulcers (DU) have even greater impairments in endothelial function compared to those without DU. FMD testing potentially has clinical utility to identify SSc patients at risk for DU an may be a promising biomarker of SSc-vasculopathy longitudinal studies. FMD may be used to describe pathogenic processes or pharmacologic response to SSc therapeutics. As such, this project will establish a solid initial base of skills and experiences that will not only develop Dr Frech as an independent clinician scientist, but will result in a careful characterization of the vasculopathy in patients with SSc through a collaborative approach and provide an endothelial targeted clinical intervention when it may have the largest potential to impact outcomes. In the first specific aim, the impact of vasculopathy on SSc patients will be assessed through patient-related and reported outcomes (PRO) and FMD testing will be performed at baseline and at 6 month intervals during clinic visits. The predictive value of FMD for the development of SSc complications (end-stage vasculopathies) will be determined. In patients who consent to skin biopsy, systemic, cellular and molecular events such as circulating and skin arteriole ROS-derived radical species, circulating and skin arteriolar markers of oxidant damage, skin arteriole expression of the oxidant enzyme NADPH oxidase and circulating antioxidants and skin arteriole expression of antioxidant enzymes will be assessed. In the second specific aim, vascular function will be assessed by measuring FMD and reactive hyperemia in patients with SSc with and without complications (i.e. end-stage vasculopathy) in the absence or presence of oral BH4 treatment for 5 days using a randomized cross-over double-blind design. In patients who consent to skin biopsy correlation analysis of oxidative stress markers will be assessed in patients with SSc with and without complications in the absence or presence of oral BH4 treatment using a randomized cross-over, double-blind design. In summary, the proposed studies will adopt an integrative approach to better define the pathophysiology of vasculopathy in SSc. We will validate a novel, non-invasive technique to evaluate vasculopathy in SSc. Additionally, we will examine if BH4, a FDA-approved drug, is effective in ameliorating vascular dysfunction in patients with SSc. Finally, to provide further mechanistic insight, we will explore the link between oxidative stress and the vascular endothelial dysfunction in SSc. If successful, these aims have the potential to improve clinical outcomes in SSc.

 描述（由适用提供）：全身性硬皮病（SSC;硬皮病）是一种复杂的自身免疫性疾病，其特征是血管变化（血管病）和疤痕（纤维化）。 SSC是一种疾病，其中血管在纤维化之前发生变化。最重要的是，早期诊断可能会改善SSC患者的预后。我们使用流量介导的词典（FMD）（一种非侵入性，客观测量的参数）的试验数据表明，与健康对照组相比，SSC患者的臂动脉直径明显较小，并且钝化的外周血管反应性和内皮功能钝化。与没有DU的SSC数字溃疡（DU）患者相比，内皮功能的损害更大。 FMD测试可能具有临床实用性，可以鉴定出有DU A的风险的SSC患者，这可能是SSC-静脉病变纵向研究的有希望的生物标志物。 FMD可用于描述对SSC治疗的致病过程或药物反应。因此，该项目将建立技能和经验的扎实初始基础，不仅将发展Frech作为独立的临床科学家，而且会通过协作方法仔细地表征SSC患者的血管疾病，并提供内皮的临床干预措施，何时可能会在首次进行特定目标中进行对SSCSSSSSC的影响，并在SSCSSSSSSSSC的影响下具有最大的潜力（ FMD测试将在基线和诊所就诊期间以6个月的间隔进行。 FMD在SSC并发症（终阶段血管病）开发中的预测价值将得到确定。在同意皮肤活检，全身性，细胞和分子事件的患者中，例如循环和小动脉ROS衍生的激进物种，氧化剂损伤的循环和皮肤小动脉标记，氧化剂酶无氧化剂的氧化剂氧化酶表达和循环抗氧化剂的抗氧化剂和皮肤表达的抗氧化剂的表达。在第二个特定目的中，将通过在不存在或没有口服BH4治疗的情况下，使用随机的交叉跨越双盲设计来评估有或没有并发症的SSC患者的FMD和反应性充血（即终末期血管病），以评估血管功能。在同意对皮肤活检相关性分析的患者中，将使用随机交叉，双盲设计在缺乏或存在口服BH4治疗的情况下进行SSC患者进行氧化应激标志物的评估。总而言之，拟议的研究将采用一种综合方法来更好地定义SSC中血管病的病理生理。我们将验证一种新型的非侵入性技术来评估SSC中的血管病。此外，我们将检查FDA批准的药物BH4是否有效地改善SSC患者的血管功能障碍。最后，为了提供进一步的机械见解，我们将探索SSC中氧化应激与血管内皮功能障碍之间的联系。如果成功，这些目标有可能改善SSC中的临床结果。