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
基本信息
- 批准号:10426267
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcuteAdhesionsAffectAgeAnimal ModelApoptosisApoptoticArteriesAutoantibodiesAutoimmune DiseasesBiopsyBloodBlood VesselsBlood capillariesBlood flowCalcinosisCell LineCell modelCellsClinicalClinical ResearchClinical assessmentsClinical effectivenessComplexComplicationCutaneousCutaneous sclerosisDataDermalDevelopmentDiagnosisDiffuseDigestive System DisordersDiseaseEndothelial CellsEndotheliumEtiologyFibroblastsFibrosisFrequenciesFunctional disorderGastrointestinal tract structureGlycocalyxGoalsHealthHomeostasisHospital CostsHumanImmuneImmunologicsImpairmentIn VitroInterventionKidneyLeukocyte RollingLeukocytesMalnutritionMeasurementMeasuresMethodsMicroscopeMicroscopicMicroscopyMicrovascular DysfunctionMilitary PersonnelModelingMonitorMorbidity - disease rateNatural HistoryOral cavityOrganOxidative StressPathogenesisPatient Outcomes AssessmentsPatientsPermeabilityPersonsPhenotypePredictive ValuePrevalencePrognosisPulmonary HypertensionQuality of lifeRare DiseasesResearchSclerodermaSignal TransductionSkinSymptomsSystemic SclerodermaSystemic diseaseTestingTherapeuticTherapeutic StudiesThickThrombosisTimeTissuesUlcerVascular DiseasesVascular EndotheliumVascular PermeabilitiesVeteransVeterans Health AdministrationVideo MicroscopyVisitWorkarteriolebody systembrachial arteryclinical practicecomparison controldensitydigitaldisease mechanisms studyeffective therapyendothelial dysfunctionendothelial stem cellevidence basehealinghealth assessmentimmune cell infiltrateimprovedin vitro testingin vivoinduced pluripotent stem cellinsightmortalitymouse modelnovelperipheral bloodpreventprogramssexstem cell modelstem cellssymptomatologytargeted treatmenttherapeutic evaluationtooltrial designwound healing
项目摘要
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,没有治愈或有效的治疗方法。
治疗疾病的许多破坏性方面。小鼠模型不能概括SSc的所有特征,
要求进行人类研究以了解这种复杂的发病机制。中位生存期约为11年,
SSc诊断和与SSc相关的估计国家医院费用每年超过2.75亿美元。SSc影响250
在美国每100万人中,退伍军人健康管理局的患病率高出3-4倍
患者SSc的发病机制以免疫异常、血管改变,特别是在
微血管和纤维化,但这些机制在胃肠内的原因和影响
消化道(GIT)是SSc中最常见的皮肤外器官系统受损,目前尚不清楚。
我们以前的工作得到I 01 CX 002111 -01“系统性硬化症(SSc)血管病变:改善”的支持
临床监测和治疗”发现两个大动脉(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的关键特征。一个功能失调
内皮导致血管通透性增加,组织免疫细胞浸润增加,血管生成减弱,
容量和受损的血管反应性和组织血流。虽然我们证明了我们可以大幅提高
这种血管功能障碍,临床干预受到试验设计问题的限制,并通过以下方法得到极大改善:
专门研究疾病机制的模型。我们发现了一种新的方法,
口腔中的微血管变化(舌下视频显微镜检查)与SSc中的GIT症状相关。
这种舌下视频显微镜测量糖萼,它维持脉管系统的稳态,
包括控制血管渗透性和微血管张力,防止微血管血栓形成,
调节白细胞粘附。
在我们提出的研究的第一个具体目标中,我们将进行糖萼的自然历史研究,
其与GIT患者报告结局(PRO)和终末期血管病变特征(包括指端溃疡)的关系
(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
为了实现这项研究的具体目标,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、毛细血管扩张和严重GIT症状)。我们将
从他们的血液和年龄产生的诱导性多能干细胞(iPSC)产生内皮细胞(EC)-
频率和性别匹配的健康对照。该项目的主要研究目标是建立在我们的
我们目前针对患有SSc的退伍军人的临床研究项目已经确定了SSc的重要体内方面
血管病变及其与PRO的关系此项目更新的最终目标是定义SSc-GIT
血管病变通过一系列微血管测量在脉管系统的口腔和相关的这些
症状、终末期血管病变临床特征和糖萼表征。然后我们将调查
终末期血管并发症的病因,通过建立一个SSc-iPSC-EC模型,可以
测试渗透性、愈合和白细胞滚动。因此,本提案将阐明SSc血管病变
通过系列舌下微血管显微镜检查,GIT PRO,糖萼功能障碍的标志物,
以及测试从外周血产生的SSc-iPSC-EC。这种血管病变特征可能
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
筛选这种破坏性的疾病,影响我们的退伍军人的生活质量,我们目前有
对发病机理的了解非常有限。重要的是,该项目中开发的新型iPSC模型具有
潜在的用于其他罕见疾病的特点是血管功能障碍,影响我们的退伍军人。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Tracy Minan Frech其他文献
Tracy Minan Frech的其他文献
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{{ truncateString('Tracy Minan Frech', 18)}}的其他基金
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:
10613002 - 财政年份:2022
- 资助金额:
-- - 项目类别:
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 - 财政年份:2022
- 资助金额:
-- - 项目类别:
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 - 财政年份:2016
- 资助金额:
-- - 项目类别:
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