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 在这次更新中,我们试图了解镰状细胞病(Scd)的异质性的起源,这是存在的。 在从分子到临床的各个层面上,它是临床管理和 开发新的治疗方法。此外,治疗往往会增加异质性,一些患者会做出反应。 对治疗反应强烈,其他人反应迟钝。我们的中心假设是异质性起源于 镰刀状血红蛋白(HBS)自组装的细胞内动力学研究 红细胞,驱动全血中强烈的非牛顿流体行为和体循环改变 这会导致内皮损伤、血管闭塞、动脉瘤和中风等病理变化。因此,能够 指导治疗干预和开发新疗法最终受到我们有限的理解的阻碍 在SCD病理生理学多尺度生物物理过程的背景下的异质性。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, 这在每个尺度上都得到了实验验证,这使我们能够预测多尺度的影响 异质性。具体地说,我们将:(1)开发HBS聚合的量化框架, 准确地预测了自组装的动力学;(2)定义了自组装的分布之间的联系 红细胞群体中的HBS聚合物和机械性能;(3)了解细胞 异质性导致非牛顿血液流变性和体循环中流动的改变。这个 此次续订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 Self- 组装动力学以前被低估了至少一个数量级;HBS聚合物 在有限氧分压下,红细胞呈不均匀分布;镰刀状血中的速度曲线显示很强 非牛顿效应;SCD患者的血流在整个循环中发生改变,并伴有异常的大管壁 相对健康血液的切应力。这项工作还利用了我们拥有的一套独特的、使人信服的工具 在过去三年的资助中开发的:单个HBS的最高时空分辨率测量 迄今为止的纤维组装;第一个能够在大量单一红细胞中定量检测HBS聚合物的平台 在定义明确的氧分压下;能够量化大量人群的粘弹性特性的平台 在明确定义的氧分压下的红细胞;量化流动的血液中亚微米速度场的能力 生理性红细胞压积;一个量化生理性氧梯度内镰状血流量的平台。在基础上建设 这些工具和见解,此次更新工作将开发和验证一个描述如何 异质性从分子到细胞再到系统,我们将开发实验工具 可用于临床管理和治疗开发。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

David Kevin Wood其他文献

David Kevin Wood的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:

相似海外基金

Establishment of human abdominal aortic aneurysm wall strength prediction model using Ex Vivo Superparamagnetic Iron Oxide–Enhanced Magnetic Resonance Imaging
利用Ex Vivo超顺磁性氧化铁建立人体腹主动脉瘤壁强度预测模型
  • 批准号:
    23K08226
  • 财政年份:
    2023
  • 资助金额:
    $ 60.62万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Endothelial Cell Reprogramming in Familial Intracranial Aneurysm
家族性颅内动脉瘤的内皮细胞重编程
  • 批准号:
    10595404
  • 财政年份:
    2023
  • 资助金额:
    $ 60.62万
  • 项目类别:
Vascular Smooth Muscle Protein Quality Control and Aortic Aneurysm Formation
血管平滑肌蛋白质量控制与主动脉瘤形成
  • 批准号:
    10714562
  • 财政年份:
    2023
  • 资助金额:
    $ 60.62万
  • 项目类别:
Enhanced Biochemical Monitoring for Aortic Aneurysm Disease
加强主动脉瘤疾病的生化监测
  • 批准号:
    10716621
  • 财政年份:
    2023
  • 资助金额:
    $ 60.62万
  • 项目类别:
Role of mechanical heterogeneity in cerebral aneurysm growth and rupture
机械异质性在脑动脉瘤生长和破裂中的作用
  • 批准号:
    10585539
  • 财政年份:
    2023
  • 资助金额:
    $ 60.62万
  • 项目类别:
Study on development of prophylaxis for recanalization after coil embolization of cerebral aneurysm and elucidation of its mechanisms
脑动脉瘤弹簧圈栓塞术后再通预防措施的研究进展及机制阐明
  • 批准号:
    23K08512
  • 财政年份:
    2023
  • 资助金额:
    $ 60.62万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Roles of aging and cellular senescence in the development of intracranial aneurysm rupture
衰老和细胞衰老在颅内动脉瘤破裂发展中的作用
  • 批准号:
    10680060
  • 财政年份:
    2023
  • 资助金额:
    $ 60.62万
  • 项目类别:
Role of Selective Autophagy of Focal Adhesion in Intracranial Aneurysm
局部粘连选择性自噬在颅内动脉瘤中的作用
  • 批准号:
    10586692
  • 财政年份:
    2023
  • 资助金额:
    $ 60.62万
  • 项目类别:
Vascular smooth muscle cell ferroptosis and abdominal aortic aneurysm
血管平滑肌细胞铁死亡与腹主动脉瘤
  • 批准号:
    10733477
  • 财政年份:
    2023
  • 资助金额:
    $ 60.62万
  • 项目类别:
Extracellular Vesicle Delivery System for Treatment of Abdominal Aortic Aneurysm
细胞外囊泡递送系统治疗腹主动脉瘤
  • 批准号:
    10751123
  • 财政年份:
    2023
  • 资助金额:
    $ 60.62万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了