Developing a multiscale understanding of biophysical processes in sickle cell disease

建立对镰状细胞病生物物理过程的多尺度理解

• 批准号: 10209656
• 负责人: David Kevin Wood
• 金额: $ 59.28万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10209656
• 关键词: 3-Dimensional; Aneurysm; Behavior; Biological Assay; Biophysical Process; Biophysics; Blood; Blood Circulation; Blood Vessels; Blood flow; Cells; Chronic; Clinic; Clinical; Clinical Management; Communities; Development; Endothelium; Fiber; Functional disorder; Funding; Growth; Hematocrit procedure; Hemoglobin; Heterogeneity; Image; Individual; Injury; Kinetics; Label; Link; Liquid substance; Measurement; Microscopy; Modeling; Molecular; Oxygen; Pathology; Patients; Physiological; Polymers; Population; Population Heterogeneity; Property; Resolution; Role; Sickle Cell Anemia; Sickle Hemoglobin; Stroke; Structure; System; Testing; Therapeutic Intervention; Transfusion; Translating; Whole Blood; Work; acute chest syndrome; blood rheology; gene therapy; hydroxyurea; insight; mechanical properties; multi-scale modeling; novel therapeutics; polymerization; self assembly; shear stress; sickling; spatiotemporal; submicron; therapeutic development; tool; viscoelasticity

PROJECT SUMMARY In this renewal, we seek to understand the origin of heterogeneity in sickle cell disease (SCD), which is present at every scale from molecules to the clinic, and is the major impediment to clinical management and the development of new therapies. Moreover, therapy often increases heterogeneity, with some patients responding strongly to therapy and others unresponsive. Our central hypothesis is that heterogeneity originates with intracellular kinetics of sickle hemoglobin (HbS) self-assembly that translates into heterogeneous populations of RBCs, which drive strong non-Newtonian fluid behavior in whole blood and alterations in the systemic circulation that precipitate pathologies such as endothelial injury, vaso-occlusion, aneurysm, and stroke. Thus, the ability to guide therapeutic intervention and to develop new therapies is ultimately hindered by our limited understanding of heterogeneity in the context of multiscale biophysical processes in SCD pathophysiology. In this work, we will develop a biophysical framework for SCD pathophysiology that spans from molecules to the systemic circulation, that is experimentally validated at every scale, and that allows us to predict the effects of multiscale heterogeneity. Specifically, we will: (1) Develop a quantitative framework for HbS polymerization that accurately predicts the kinetics of self-assembly; (2) Define the connection between the distribution of HbS polymer and mechanical properties among a population of RBCs; (3) Understand how cellular heterogeneity drives non-Newtonian blood rheology and altered flow in the systemic circulation. The work in this renewal builds on key conceptual advances made during our last 3 years of funding: HbS self- assembly kinetics have previously been underestimated by at least an order of magnitude; HbS polymer is heterogeneously distributed in RBCs at finite oxygen tension; velocity profiles in sickle blood demonstrate strong non-Newtonian effects; blood flow in SCD patients is altered throughout the circulation with aberrantly large wall shear stress relative to healthy blood. This work also leverages a unique and enabling set of tools that we have developed during the last 3 years of funding: the highest spatiotemporal resolution measurements of single HbS fiber assembly to-date; the first platform capable of quantifying HbS polymer in large populations of single RBCs under well-defined oxygen tension; a platform capable of quantifying viscoelastic properties of large populations of RBCs under well-defined oxygen tension; the ability to quantify submicron velocity fields in flowing blood at physiologic hematocrit; a platform to quantify sickle blood flow within physiologic oxygen gradients. Building on these tools and insights, this renewal work will develop and validate a multiscale model describing how heterogeneity propagates from the molecular to cellular to system levels, and we will develop experimental tools that can be used for clinical management and therapeutic development.

项目摘要 在这种续约中，我们试图了解存在的镰状细胞病（SCD）中异质性的起源 在从分子到诊所的每个规模上，都是临床管理和 开发新疗法。此外，治疗通常会增加异质性，一些患者反应 强烈对治疗和其他人无反应。我们的中心假设是异质性起源于 镰状血红蛋白（HBS）自组装的细胞内动力学，转化为异质种群 RBC，在全血和全身循环的改变中驱动强烈的非牛顿流体行为 这会导致病理，例如内皮损伤，血管咬合，动脉瘤和中风。因此，能够 我们有限的理解最终阻碍了治疗干预并开发新疗法 SCD病理生理学中多尺度生物物理过程的异质性。在这项工作中，我们将 为SCD病理生理学开发生物物理框架，该框架从分子到全身循环， 这在每个规模上都经过实验验证，这使我们能够预测多尺度的影响 异质性。具体而言，我们将：（1）开发一个定量框架以进行HBS聚合，以便 准确地预测自组装的动力学； （2）定义分布之间的连接 RBC人群中的HBS聚合物和机械性能； （3）了解细胞如何 异质性驱动非牛顿血流变学和全身循环中的流动改变。这 在我们过去三年的资金中取得的关键概念进步基于此续签：HBS自我 以前，至少一个数量级来低估了组装动力学。 HBS聚合物是 异质分布在有限氧张力下的RBC中；镰状血中的速度曲线表现出很强的 非牛顿效应；在整个循环中，SCD患者的血流发生了变化，异常大的壁 相对于健康血液的剪切应力。这项工作还利用了我们拥有的独特而有利的工具 在资金的最后三年中开发：单个HBS的最高时空分辨率测量 迄今为止的纤维组件；第一个能够量化大量单个RBC中HBS聚合物的平台 在明确定义的氧气张力下；一个能够量化大量人群的粘弹性特性的平台 定义明确的氧气张力下的RBC；在流动血液中量化亚微米速度场的能力 生理血细胞比容；一个量化生理氧梯度内镰状血流的平台。建立 这些工具和见解，这项更新工作将开发和验证一个多尺度模型，描述如何描述如何 异质性从分子到细胞到系统水平传播，我们将开发实验工具 可以用于临床管理和治疗发展。