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.

项目概要 在本次更新中，我们试图了解镰状细胞病 (SCD) 中存在的异质性的起源 从分子到临床的各个层面，这是临床管理和临床治疗的主要障碍 新疗法的开发。此外，治疗常常会增加异质性，一些患者会做出反应 对治疗强烈而其他人反应迟钝。我们的中心假设是异质性源于 镰状血红蛋白 (HbS) 自组装的细胞内动力学，转化为异质群体 红细胞，驱动全血中强烈的非牛顿流体行为和体循环的改变 导致内皮损伤、血管闭塞、动脉瘤和中风等病变。因此，能够 指导治疗干预和开发新疗法最终会受到我们有限的理解的阻碍 SCD 病理生理学多尺度生物物理过程背景下的异质性。在这项工作中，我们将 为 SCD 病理生理学开发一个从分子到体循环的生物物理框架， 这在每个尺度上都经过实验验证，这使我们能够预测多尺度的影响 异质性。具体来说，我们将： (1) 开发 HbS 聚合的定量框架 准确预测自组装动力学； (2) 定义分布之间的联系 红细胞群体中的 HbS 聚合物和机械特性； (3)了解细胞如何 异质性驱动非牛顿血液流变学并改变体循环中的流量。这 此次更新的工作建立在我们过去 3 年资助期间取得的关键概念进展的基础上：HbS 自 组装动力学以前被低估了至少一个数量级； HbS 聚合物是 在有限氧张力下，红细胞中分布不均匀；镰刀血中的速度分布显示出很强的 非牛顿效应； SCD 患者的整个循环血流发生改变，血管壁异常变大 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一套独特且有效的工具 在过去 3 年的资助中开发的：单个 HbS 的最高时空分辨率测量 最新的纤维组装；第一个能够量化大量单一红细胞中 HbS 聚合物的平台 在明确的氧分压下；能够量化大量群体粘弹性特性的平台 红细胞在明确的氧分压下；量化流动血液中亚微米速度场的能力 生理血细胞比容；一个在生理氧梯度内量化镰刀血流量的平台。建立在 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 异质性从分子到细胞再到系统水平传播，我们将开发实验工具 可用于临床管理和治疗开发。