Biomarkers of Cerebral Cavernous Angioma with Symptomatic Hemorrhage (CASH)

伴有症状性出血的脑海绵状血管瘤 (CASH) 的生物标志物

• 批准号: 10055845
• 负责人: ISSAM A AWAD
• 金额: $ 68.97万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10055845
• 关键词: Affect; Age; Algorithms; American; Anticoagulants; Automobile Driving; Behavior; Benchmarking; Benign; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Tests; Blood Vessels; Blood capillaries; Brain Pathology; Brain hemorrhage; Cavernous Hemangioma; Cerebrovascular Disorders; Cerebrum; Characteristics; Clinical; Clinical Management; Clinical Trials; Complement; Complex; Computational Biology; Cross-Sectional Studies; Data; Data Element; Deposition; Diagnosis; Diagnostic; Diagnostic Sensitivity; Discriminant Analysis; Disease; Enrollment; Exhibits; Future; Genetic; Genotype; Goals; Hemorrhage; IL6 gene; Image; Immune; Individual; Inflammation; Inflammatory; Interleukin-1 beta; Iron; Knowledge; Lesion; Machine Learning; Magnetic Resonance Imaging; Measures; Mediating; Modeling; Monitor; Natural Immunity; Patients; Perfusion; Peripheral; Pilot Projects; Plasma; Plasma Proteins; Population; Predisposition; Process; Proteins; RNA; Readiness; Research; Research Personnel; Risk; Sampling; Seizures; Sensitivity and Specificity; Signal Transduction; Site; Subgroup; Techniques; Testing; Time; Uncertainty; Validation; Variant; Vascular Diseases; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vitamin D Deficiency; accurate diagnosis; angiogenesis; base; biomarker development; biomarker discovery; candidate marker; clinical application; clinically relevant; cohort; contrast enhanced; data harmonization; disorder subtype; follow-up; gut microbiome; high risk; imaging biomarker; indexing; machine learning algorithm; microbiome; nervous system disorder; neurovascular unit; novel; novel marker; outcome forecast; peripheral blood; premature; prognostic; prognostic value; recruit; response; sex; statistics; supervised learning; support vector machine; synergism; therapeutic development; transcriptome

Biomarkers of Cerebral Cavernous Angioma with Symptomatic Hemorrhage (CASH) PROJECT SUMMARY Cerebral cavernous angioma (CA) is a capillary microangiopathy affecting more than a million Americans, predisposing them to a premature risk of brain hemorrhage. Fewer than 200,000 cases who have suffered a recent symptomatic hemorrhage (SH) are most likely to re-bleed again with serious clinical sequelae, and are the primary focus of therapeutic development. Genetic mechanisms of CA have been extensively studied, and consequent signaling aberrations in the neurovascular unit. These include proliferative dysangiogenesis, blood- brain barrier hyperpermeability, inflammation and immune mediated processes, anticoagulant vascular domain, and gut microbiome-driven mechanisms. Plasma levels of molecules reflecting these mechanisms and measures of vascular permeability and hemorrhage leak on magnetic resonance imaging (MRI) have been correlated with CA hemorrhage in pilot studies. It would be desirable to optimize these biomarkers to accurately diagnose CASH, to prognosticate the risk of future SH, and to monitor cases after a bleed and in response to therapy. This would influence clinical management, and select higher risk cases for clinical trials. Additional candidate biomarkers are emerging from ongoing mechanistic and differential transcriptome studies, which would be expected to further enhance the sensitivity and specificity of diagnosis and prediction of CASH. Weighed combinations of levels of plasma proteins and characteristic micro-ribonucleic acids (miRNA) may further strengthen biomarker associations. Plasma biomarkers may reflect (and potentially replace) more cumbersome and expensive imaging biomarkers for monitoring CA hemorrhage. We here assemble leading clinical CA researchers and propose to deploy advanced statistical and computational biology approaches (including supervised machine learning) for the integration of novel candidate biomarkers, rejecting non-correlated candidates, and determining the best clustering and weighing of combined biomarker contributions. In Specific Aim 1 we assess these biomarkers in a large CA cohort from multiple sites, to discover the best plasma biomarkers and validate them in sex, age and relevant clinical subgroups. In Specific Aim 2 we compare changes in MRI measures of vascular permeability and hemorrhage with plasma biomarkers over time. In Specific Aim 3 we query the biomarkers in non-CA subjects, to identify potential confounders in the clinical context. This project leverages the synergy of established CA research consortia, and integrates analytic and computational biology expertise to develop blood tests for better CASH diagnosis and prognosis. The project tests a novel integrational approach of biomarker development in a mechanistically defined cerebrovascular disease with a relevant context of use. This approach is applicable to other neurological diseases with similar pathobiologic features.

有症状出血（现金）的脑海绵状血管瘤的生物标志物 项目摘要 脑海绵状血管瘤（CA）是一种毛细管微血管病，影响超过一百万美国人， 使它们易于过早出血。少于200,000例遭受的案件 最近有症状的出血（SH）最有可能再次以严重的临床后遗症重新出血，并且是 治疗发展的主要重点。 CA的遗传机制已被广泛研究，并且 导致神经血管单元中的信号畸变。这些包括增生性障碍症，血液 - 脑屏障超透明度，炎症和免疫介导的过程，抗凝血管结构域， 和肠道微生物组驱动的机制。反映这些机制和测量的分子的血浆水平 磁共振成像（MRI）上血管通透性和出血泄漏已与 试点研究中的CA出血。希望优化这些生物标志物以准确诊断现金， 预测未来SH的风险，并在出血后监测病例并响应治疗。这会 影响临床管理，并为临床试验选择更高的风险病例。其他候选生物标志物 正在从正在进行的机械和差异转录组研究中出现，这将有望 进一步提高了诊断和现金预测的敏感性和特异性。称重的组合 血浆蛋白和特征性微核酸（miRNA）的水平可以进一步增强生物标志物 协会。等离子体生物标志物可能反映（并有可能取代）更繁琐且昂贵的成像 监测CA出血的生物标志物。我们在这里组装领先的临床研究人员，并建议 部署高级统计和计算生物学方法（包括监督机器学习） 新型候选生物标志物的整合，拒绝无关的候选人，并确定最佳 聚类和称重生物标志物贡献。在特定目标1中，我们评估了这些生物标志物 来自多个站点的大型CA队列，以发现最好的等离子生物标志物，并在性别，年龄和 相关的临床亚组。在特定目标2中，我们比较了血管通透性的MRI测量的变化 随着时间的流逝，血浆生物标志物出血。在特定目标3中，我们在非CA中查询生物标志物 受试者，在临床背景下识别潜在的混杂因素。该项目利用已建立的协同作用 CA研究联盟，并整合分析和计算生物学专业知识，以开发血液检查 更好的现金诊断和预后。该项目测试了一种新型生物标志物的整合方法 在机械定义的脑血管疾病中发育，并具有相关的使用背景。这种方法 适用于具有类似病原体特征的其他神经系统疾病。