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

基本信息

  • 批准号:
    10673595
  • 负责人:
  • 金额:
    $ 60.62万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
项目总结

项目成果

期刊论文数量(0)
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David Kevin Wood其他文献

David Kevin Wood的其他文献

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{{ truncateString('David Kevin Wood', 18)}}的其他基金

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:
    10756268
  • 财政年份:
    2017
  • 资助金额:
    $ 60.62万
  • 项目类别:
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
  • 财政年份:
    2017
  • 资助金额:
    $ 60.62万
  • 项目类别:
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:
    10382453
  • 财政年份:
    2017
  • 资助金额:
    $ 60.62万
  • 项目类别:
A microfluidic platform to study sickle blood rheology
研究镰状血液流变学的微流控平台
  • 批准号:
    9684422
  • 财政年份:
    2017
  • 资助金额:
    $ 60.62万
  • 项目类别:
Dissecting the origins of fetal hemoglobin modulation of sickle cell vaso-occlusion
剖析胎儿血红蛋白调节镰状细胞血管闭塞的起源
  • 批准号:
    9258476
  • 财政年份:
    2016
  • 资助金额:
    $ 60.62万
  • 项目类别:
Carcinoma Cell Hyaluronan as a Therapeutic Target in Metastasis
癌细胞透明质酸作为转移治疗靶点
  • 批准号:
    9250092
  • 财政年份:
    2016
  • 资助金额:
    $ 60.62万
  • 项目类别:
A microfluidic platform to study sickle blood rheology
研究镰状血液流变学的微流控平台
  • 批准号:
    9324460
  • 财政年份:
    2016
  • 资助金额:
    $ 60.62万
  • 项目类别:
Carcinoma Cell Hyaluronan as a Therapeutic Target in Metastasis
癌细胞透明质酸作为转移治疗靶点
  • 批准号:
    9100026
  • 财政年份:
    2016
  • 资助金额:
    $ 60.62万
  • 项目类别:
Self-Organized Tissue Microvasculature
自组织组织微脉管系统
  • 批准号:
    7614893
  • 财政年份:
    2009
  • 资助金额:
    $ 60.62万
  • 项目类别:
Self-Organized Tissue Microvasculature
自组织组织微脉管系统
  • 批准号:
    7787518
  • 财政年份:
    2009
  • 资助金额:
    $ 60.62万
  • 项目类别:

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