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

• 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
• 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

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）：以纯合形式称为镰状细胞性贫血的镰状细胞疾病（SCD）影响50名非裔美国人中有1个具有令人衰弱的，慢性，危机发作，并降低了预期寿命。 SCD是由β-珠蛋白基因中的单点突变引起的遗传性血液疾病。镰状血红蛋白（HBS）具有在脱氧时具有聚合的独特特性，引发了红细胞（RBC）晕车和脱水，从而导致毛细血管和小血管中的血管酸性和血流受损。体外HBS聚合的生物化学已充分了解。然而，在RBC内部，由于缺乏适当的测量方法和现实模型，因此对HBS聚合产生的细胞力学变化和粘附性能的基本变化的机制很少。三个具有生物光谱学互补专业知识的研究团队（由Peter So，MIT领导），生物力学和微流体学（由Ming Dao，MIT领导）和SCD治疗（由Gregory Kato的领导，UPMC领导）将加入力量，以开发可以量化RBC Biomechanics在RBC生病期的技术。虽然有许多因素导致了血管结合，但众所周知，RBC生物力学起着关键作用。预测性血管辨别模型的开发将加深我们对SCD病因的理解，从而在系统层面上，从而开发出更有效的药物和治疗方法。 朝向这些目标，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。这些技术将使我们能够以精确控制的氧合水平在微流体设备内部的寒假过渡期间以前所未有的精度来量化RBC的流变特性。我们将进一步开发基于互补的显微镜光谱方法，以量化HBS氧合和聚合状态。与HBS生化状态变化的RBC形状和流变学变化的同时测量应使我们能够更好地理解细胞内分子水平变化如何驱动RBC生物力学，这是血管估计和SCD危机的关键因素。该方法的能力将在试点研究中评估，以阐明羟基脲的治疗机制，羟基脲是唯一专门用于SCD的FDA批准的药物，以及正在开发的新药物AES -103。这些研究将建立原则证明，证明该平台可以用于筛查新的反ic贴药物。 UPMC镰状细胞疾病注册中心将提供丰富的临床数据库，以注释患者标本，该标本将通过晚期RBC生物力学分析进行分析。这将允许临床特征与从生物力学测定法获得的潜在生物标志物的初步探索性统计相关性。