Characterizing mechanisms of sickle cell crisis via dynamic optical assay

通过动态光学测定表征镰状细胞危机的机制

基本信息

批准号：
8927051
负责人：
Peter T. So
金额：
$ 54.03万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8927051
关键词：
3-Dimensional Accounting Adhesions Advocate Affect African American Anisotropy Biochemical Biochemistry Biological Biological Assay Biological Markers Biomechanics Blood Vessels Blood capillaries Blood flow Blood specimen Cell Shape Cells Characteristics Chemicals Chest Pain Chronic Clinical Companions Correlation Studies Crystallization Data Databases Dehydration Development Diagnostic Disease model Effectiveness Erythrocytes Etiology Event FDA approved Functional disorder Genes Globin Goals Health Hematological Disease Hemoglobin Imaging technology In Vitro Individual Inherited Interdisciplinary Study Lead Life Expectancy Link Measurement Measures Mechanics Membrane Methods Microfluidic Microchips Microfluidics Microscope Microscopy Modeling Molecular Noise Nucleotides Optics Outcome Oxygen Partial Pressure Patients Pharmaceutical Preparations Phase Phase II Clinical Trials Pilot Projects Play Point Mutation Process Property Research Resolution Rheology Risk Sampling Shapes Sickle Cell Sickle Cell Anemia Sickle Hemoglobin Signal Transduction Specimen Speed Stroke System Technology Therapeutic Time United States Variant Vision base beta Globin biomechanical model capillary disease registry hemodynamics human data hydroxyurea improved in vivo millisecond multi-scale modeling novel particle photonics polymerization screening sickle cell crisis sickling tool

项目摘要

DESCRIPTION (provided by applicant): Sickle cell disease (SCD), known in the homozygous form as sickle cell anemia, affects 1 in 50 African Americans with debilitating, chronic, crisis episodes and reduced life expectancy. SCD is an inherited blood disorder caused by a single point mutation in the beta-globin gene. Sickle hemoglobin (HbS) has the unique property of polymerizing when deoxygenated, triggering red blood cell (RBC) sickling and dehydration, leading to vaso-occlusion and impaired blood flow in capillaries and small vessels. The biochemistry of HbS polymerization in vitro is well understood. However, inside RBC, the mechanism of underlying changes in cell mechanics and adhesion properties resulting from HbS polymerization is poorly understood due to a lack of appropriate measurement methods and realistic models. Three research teams with complementary expertise in bio-photonics (lead by Peter So, MIT), in biomechanics and microfluidics (lead by Ming Dao, MIT), and in SCD treatment (lead by Gregory Kato, UPMC) will join force to develop technologies that can quantify RBC biomechanics during RBC sickling. While there are many factors contributing to vaso-occlusion, RBC biomechanics is known to play a key role. The development of a predictive vaso-occlusion model will deepen our understanding of SCD etiology on a system level allowing the development of more effective drugs and treatments. Toward these goals, our team will develop reflection mode quantitative phase microscopy and a 3-D dissipative particle dynamics (DPD) multi-scale model. These technologies together will allow us to quantify RBC rheological properties with unprecedented accuracy during sickling transition inside microfluidic devices with precisely controlled oxygenation level. We will further develop complementary phase microscopy based spectroscopic methods to quantify HbS oxygenation and polymerization states. Simultaneous measurement of changes in RBC shape and rheology with changes in HbS biochemical states should allow us to better understand how intracellular molecular level variations drive RBC biomechanics, a key factor in vaso-occlusion and SCD crisis. The power of this approach will be evaluated in pilot studies to elucidate the therapeutic mechanisms of hydroxyurea, the only FDA approved drug specifically for SCD, and Aes -103, a new drug under development. These studies will develop proof of principle that this platform could be utilized in screening new anti-sickling drugs. The UPMC sickle cell disease registry will provide a rich clinical database to annotate the patient specimens that will be analyzed by advanced RBC biomechanics assays. This will allow preliminary exploratory statistical correlation of clinical characteristics to the potential biomarkers derived from the biomechanics assays.

描述（由申请人提供）：镰状细胞病（SCD），以纯合子形式被称为镰状细胞性贫血，影响五分之一的非裔美国人，导致衰弱、慢性、危机发作和预期寿命缩短。 SCD 是一种遗传性血液疾病，由 β 珠蛋白基因的单点突变引起。镰状血红蛋白 (HbS) 具有独特的性质，在脱氧时会聚合，引发红细胞 (RBC) 镰状化和脱水，导致血管闭塞以及毛细血管和小血管中的血流受损。 HbS 体外聚合的生物化学是众所周知的。然而，在红细胞内部，由于缺乏适当的测量方法和现实模型，人们对 HbS 聚合引起的细胞力学和粘附特性的潜在变化机制知之甚少。三个在生物光子学（由麻省理工学院的 Peter So 领导）、生物力学和微流体学（由麻省理工学院的 Ming Dao 领导）和 SCD 治疗（由 UPMC 的 Gregory Kato 领导）领域拥有互补专业知识的研究团队将联手开发技术可以量化红细胞镰状化期间的红细胞生物力学。虽然导致血管闭塞的因素有很多，但众所周知，红细胞生物力学起着关键作用。预测性血管闭塞模型的开发将加深我们对系统性猝死病因的理解，从而开发出更有效的药物和治疗方法。为了实现这些目标，我们的团队将开发反射模式定量相显微镜和 3D 耗散粒子动力学 (DPD) 多尺度模型。这些技术共同将使我们能够在微流体装置内镰状转变期间以前所未有的精度量化红细胞流变特性，并精确控制氧合水平。我们将进一步开发基于互补相位显微镜的光谱方法来量化 HbS 氧合和聚合状态。同时测量红细胞形状和流变学的变化以及 HbS 生化状态的变化，应该能让我们更好地了解细胞内分子水平的变化如何驱动红细胞生物力学，这是血管闭塞和 SCD 危机的关键因素。这种方法的功效将在试点研究中进行评估，以阐明羟基脲（FDA 批准的唯一专门用于 SCD 的药物）和 Aes -103（一种正在开发的新药）的治疗机制。这些研究将证明该平台可用于筛选新的抗镰状病药物。 UPMC 镰状细胞病登记处将提供丰富的临床数据库来注释将通过先进的红细胞生物力学测定进行分析的患者标本。这将允许临床特征与生物力学测定中衍生的潜在生物标志物进行初步探索性统计相关。