Multimodal biophysical markers of vascular disease in hemoglobinopathies

血红蛋白病中血管疾病的多模式生物物理标志物

• 批准号: 8830540
• 负责人: THOMAS Duane COATES
• 金额: $ 0.48万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8830540
• 关键词: Accounting; Anemia; Autonomic nervous system; Behavioral Research; Biological Markers; Biomedical Engineering; Biophysics; Blood Vessels; Cardiac; Cardiac Output; Cardiology; Cerebrum; Chemistry; Chronic; Communities; Complex; Computer Simulation; Defect; Discipline; Disease; Equilibrium; Genes; Goals; Hematological Disease; Hematology; Hemoglobinopathies; Measurement; Measures; Modality; Monitor; Pain; Pain Research; Patients; Peripheral; Physiological; Physiology; Process; Pulmonology; Radiology Specialty; Regional Perfusion; Reporting; Research; Research Personnel; Risk; Sampling; Secondary to; Sickle Cell Anemia; Sickle Hemoglobin; Therapeutic Intervention; Transfusion; Translations; Vascular Diseases; abstracting; base; blood rheology; cellular pathology; human subject; improved; interest; molecular pathology; tool; vasoconstriction

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is characterized by painful vasoocclusive crises that occur on top of a chronic, progressive vascular disease. Advancement towards new treatment modalities for SCD has been significantly hampered by the lack of biomarkers that can effectively monitor the underlying pathophysiological processes. We have previously shown that SCD subjects have marked dysregulation of the autonomic nervous system (ANS), and that sigh and pain can cause vasoconstriction. We hypothesize that physiologically-based biomarkers reflecting regional perfusion and ANS balance report the collective effects of all molecular and cellular pathologies secondary to the gene defect in SCD. To study this hypothesis, we have assembled a group of skilled investigators from multiple disciplines (pain and behavioral research, biomedical engineering, cardiology, chemistry, hematology, physiology and biophysics, pulmonology, and radiology) to develop and calibrate biomarkers reflecting 1) cardiac ANS imbalance, peripheral and pain-triggered vasoconstriction; and 2) peripheral vascular function and regional cerebral flow and oxygenation. Another goal is to provide standardized measurement/processing tools for use by others. Our unique approach involves sampling multiple physiological variables simultaneously and using computational modeling to account for the complex interactions and isolate the biophysical biomarker of interest. Measurements will be made in human subjects with selected hematological disorders that differ in degree of anemia or blood rheology. We will also study SCD patients on chronic transfusion with varying percent hemoglobin S in order to separate the measurement components due to altered blood rheology and cardiac output from the components reflecting vascular status and the autonomic function of interest. The translation of these biomarkers and derived tools to the SCD research community will fulfill a need and be invaluable for stratifying risk, monitoring disease status, an measuring the effects of therapeutic interventions in patients with SCD. In the course of validating these biomarkers, we will improve our understanding of vascular disease in SCD and other hemoglobinopathies, as well as in normal subjects. (End of Abstract)

描述（由申请人提供）： 镰状细胞疾病（SCD）的特征是在慢性进行性血管疾病的顶部发生的疼痛血管狭窄危机。缺乏可以有效监测潜在的病理生理过程的生物标志物的缺乏生物标志物，对SCD的新治疗方式的进步受到了极大的阻碍。我们以前已经表明，SCD受试者明显地表明了自主神经系统（ANS）的失调，并且叹息和疼痛会引起血管收缩。我们假设基于生理的生物标志物反映区域灌注和ANS平衡报告了SCD基因缺陷继发的所有分子和细胞病理的集体作用。为了研究这一假设，我们组装了来自多个学科的一组熟练的研究者（疼痛和行为研究，生物医学工程，心脏病学，化学，化学，血液学，生理学和生物物理学，肺病学和放射学），以发展和校准反射的生物标志物。失衡，周围和疼痛触发的血管收缩； 2）周围血管功能以及区域脑流和氧合。另一个目标是提供标准化的测量/处理工具，以供他人使用。我们独特的方法涉及同时取样多个生理变量，并使用计算建模来说明复杂的相互作用并隔离感兴趣的生物物理生物标志物。在贫血或血流变程度不同的人类受试者中，将进行测量。我们还将研究SCD患者的慢性输血，血红蛋白的百分比不同，以将由于血液流变学和心脏输出改变而导致的测量成分与反映血管状态和感兴趣的自主权功能的成分所致。这些生物标志物和派生工具向SCD研究社区的翻译将满足需求，并且对于分层风险，监测疾病状况，测量SCD患者的治疗干预措施的影响是无价的。在验证这些生物标志物的过程中，我们将提高对SCD和其他血红蛋白病血管疾病以及正常受试者中血管疾病的理解。 （抽象的结尾）