Multimodal biophysical markers of vascular disease in hemoglobinopathies

描述（由申请人提供）： 镰状细胞病（SCD）的特征是在慢性进行性血管疾病基础上发生的疼痛性血管闭塞危象。由于缺乏能够有效监测潜在病理生理过程的生物标志物，SCD新治疗模式的进展受到严重阻碍。我们以前已经证明，SCD受试者有明显的自主神经系统（ANS）失调，叹息和疼痛可引起血管收缩。我们假设，生理学为基础的生物标志物反映区域灌注和ANS平衡报告继发于SCD基因缺陷的所有分子和细胞病理的集体效应。为了研究这一假设，我们召集了一组来自多个学科（疼痛和行为研究、生物医学工程、心脏病学、化学、血液学、生理学和生物物理学、肺病学和放射学）的熟练研究人员，以开发和校准反映1）心脏ANS失衡、外周和疼痛触发的血管收缩;和2）外周血管功能和局部脑血流和氧合的生物标志物。另一个目标是提供标准化的测量/处理工具供他人使用。我们独特的方法涉及同时对多个生理变量进行采样，并使用计算建模来解释复杂的相互作用并分离感兴趣的生物物理生物标志物。将在患有选定血液学疾病的人类受试者中进行测量，这些血液学疾病的贫血或血液流变学程度不同。我们还将研究长期输血的SCD患者，其中血红蛋白S的百分比不同，以便将由于血液流变学和心输出量改变而导致的测量成分与反映血管状态和感兴趣的自主神经功能的成分分开。将这些生物标志物和衍生工具转化为SCD研究社区将满足需求，并且对于分层风险，监测疾病状态，测量SCD患者治疗干预措施的效果非常宝贵。在验证这些生物标志物的过程中，我们将提高我们对SCD和其他血红蛋白病以及正常受试者中血管疾病的理解。(End摘要）

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)