Quantitative Analysis of Blood Flow in Sickle Cell Disease

镰状细胞病血流的定量分析

• 批准号: 8025300
• 负责人: John Matthew Higgins
• 金额: $ 15.92万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-20 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8025300
• 关键词: Behavior; Blood; Blood flow; Blood specimen; Caliber; Cell Adhesion Molecules; Cell membrane; Cellular biology; Chemicals; Clinical; Clinical Pathology; Complex; Computer Architectures; Development Plans; Devices; Disease; Doctor of Medicine; Doctor of Philosophy; Engineering; Environment; Erythrocytes; Functional disorder; Health Sciences; Hematocrit procedure; Hemoglobin; Hydration status; Image Analysis; Kinetics; Laboratories; Mathematics; Measurement; Measures; Medicine; Mentors; Microfluidic Microchips; Microfluidics; Microscopic; Modeling; Modification; Monitor; Muscle Rigidity; Osmolar Concentration; Oxygen; Oxygen measurement, partial pressure, arterial; Pathology; Patients; Phenotype; Physics; Plasma; Process; Property; Recording of previous events; Research Project Grants; Sampling; Severities; Severity of illness; Sickle Cell; Sickle Cell Anemia; Stratification; Symptoms; Systems Biology; Technology; Testing; Time; Training; Translating; Translations; Treatment Protocols; United States National Institutes of Health; Universities; Variant; Work; career; career development; computer science; environmental intervention; experience; hydroxyurea; medical schools; multi-scale modeling; novel; polymerization; pressure; professor; programs; response; sickling; skills; small molecule

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.

描述（由申请人提供）：候选人是病理学的临床研究员，提出了一项为期5年的学术临床实验室医学事业的发展计划。候选人在临床病理学，应用数学和计算机科学方面拥有培训和专业经验。哈佛医学院医学教授的H. Franklin Bunn和H.Minarayanan Mahadevan博士，哈佛大学的应用数学教授和哈佛大学系统生物学学位教授Lakshminarayanan Mahadevan博士将为他提供指导和建议。 Bunn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。 候选人的咨询小组包括M.D. M.D. Sangeeta Bhatia，MIT副教授，MIT副教授，Carlo Brugnara，医学博士，哈佛医学院病理学教授，David Dorfman，M.D。，M.D。，博士，博士，Harvard Medical School和William Eaton，M.D。 这项职业发展计划将促进他进一步获得对建模和了解血液流动障碍并将这些发现转化为临床实验室或床边所必需的理论和实用技能。该研究项目将研究镰状细胞疾病中血管牙合的原因。血管封闭是在多个尺度上发生的过程：纳米镜面血红蛋白聚合，微观细胞疾病和内皮反应以及宏观血管闭塞。血管咬合的控制参数包括血红蛋白的浓度，氧张力，血细胞比容，内皮表型，血管直径和压力梯度。将使用微流体设备和计算图像分析研究这种动态病理生理过程。初步工作表明，在有限的人造微流体环境中，唤起，逆转，扰动和抑制镰状细胞血液阻塞的能力。提出的工作将探索血管封闭的过程，其对扰动的响应以及与患者症状严重程度的相关性，通过（1）表征在现有有限的微流体设备中的闭塞动态，在一系列控制参数值下，（2）扩展了初始条件的范围，将初始条件的范围扩展，参数值和血液标本构成（3），（3）的范围（3）几何和引入小分子。 这项工作将促进我们对这种疾病过程机制的理解，并有可能立即应用于临床实验室，以监测和治疗镰状细胞患者的治疗分层。这项工作还可以用作优化现有治疗方案的测试工作台，并鉴定出全新的疗法。