Quantitative Analysis of Blood Flow in Sickle Cell Disease

描述（由申请人提供）：候选人是病理学临床研究员，提出了5年的学术临床实验室医学职业发展计划。候选人在临床病理学、应用数学和计算机科学方面有培训和专业经验。他将由H.医学博士富兰克林邦恩，哈佛医学院医学教授，以及Lakshminarayanan Mahadevan博士，哈佛大学应用数学教授和哈佛医学院系统生物学教授。邦恩博士是红细胞生物学和病理生理学领域的专家。Mahadevan教授是生物物理建模领域的专家。 候选人的顾问团队包括医学博士桑吉塔·巴蒂亚，博士，麻省理工学院健康科学与技术副教授Carlo Brugnara，医学博士，哈佛医学院病理学教授，医学博士大卫多夫曼，哲学博士、哈佛医学院病理学副教授和医学博士威廉·伊顿，博士，美国国立卫生研究院化学物理系主任。 这个职业发展计划将促进他进一步获得必要的理论和实践技能，以建模和理解血流障碍，并将这些发现转化为临床实验室或床边。该研究项目将调查镰状细胞病血管闭塞的原因。血管闭塞是发生在多个尺度水平的过程：纳米级血红蛋白聚合、微观细胞镰状化和内皮反应以及宏观血管闭塞。血管闭塞的控制参数包括血红蛋白S浓度、氧分压、血细胞比容、内皮表型、血管直径和压力梯度。这一动态病理生理过程将使用微流控装置和计算机图像分析进行研究。初步工作已经证明了在有限的人工微流体环境中唤起、逆转、扰动和抑制镰状细胞血液闭塞的能力。所提出的工作将通过以下方式探索血管闭塞的过程、其对扰动的响应以及其与患者症状严重程度的相关性：（1）在一系列控制参数值下表征现有有限微流体装置中的闭塞动力学，（2）扩大初始条件、参数值和血液样本操作的范围，以及（3）用粘附分子增强实验装置，复杂的几何形状和小分子的引入。 这项工作将促进我们对这种疾病过程的机制的理解，并可能立即应用于临床实验室，用于监测和治疗镰状细胞患者的分层。这项工作也可以作为优化现有治疗方案和识别全新疗法的测试平台。

DESCRIPTION (provided by applicant): The candidate is a clinical fellow in pathology proposing a 5-year development plan for a career in academic clinical laboratory medicine. The candidate has training and professional experience in clinical pathology, applied mathematics, and computer science. He will be mentored and advised by both H. Franklin Bunn, M.D., Professor of Medicine at Harvard Medical School, and by Lakshminarayanan Mahadevan, Ph.D., Professor of Applied Mathematics at Harvard University and of Systems Biology at Harvard Medical School. Dr. Bunn is an expert in the field of red blood cell biology and pathophysiology. Professor Mahadevan is an expert in the field of biophysical modeling. The candidate's advisory team includes Sangeeta Bhatia, M.D., Ph.D., Associate Professor of Health Sciences and Technology at MIT, Carlo Brugnara, M.D., Professor of Pathology at Harvard Medical School, David Dorfman, M.D., Ph.D., Associate Professor of Pathology at Harvard Medical School, and William Eaton, M.D., Ph.D., Chief of Chemical Physics, NIH. This career development program will promote his further acquisition of the theoretical and practical skills necessary to model and understand disorders of blood flow and to translate those findings to the clinical laboratory or the bedside. The research project will investigate the causes of vaso-occlusion in sickle cell disease. Vaso-occlusion is a process occurring at multiple levels of scale: nanoscopic hemoglobin polymerization, microscopic cellular sickling and endothelial response, and macroscopic vessel occlusion. Control parameters for vaso-occlusion include hemoglobin S concentration, oxygen tension, hematocrit, endothelial phenotype, vessel diameter, and pressure gradient. This dynamic pathophysiologic process will be studied using microfluidic devices and computational image analysis. Preliminary work has demonstrated the ability to evoke, reverse, perturb, and inhibit the occlusion of sickle cell blood in a limited artificial microfluidic environment. The proposed work will explore the process of vaso-occlusion, its response to perturbation, and its correlation with patient symptom severity by (1) characterizing the dynamics of occlusion in an existing limited microfluidic device under a range of control parameter values, (2) expanding the range of initial conditions, parameter values, and blood specimen manipulations, and (3) enhancing the experimental device with adhesion molecules, complex geometries, and the introduction of small molecules. This work will advance our understanding of the mechanism of this disease process and has potentially immediate applications for translation to the clinical laboratory for monitoring and treatment stratification of sickle cell patients. This work may also serve as a test bench for the optimization of existing treatment regimens and the identification of altogether novel therapies.