Long-Term Tracking of Cerebral Microvascular Structural and Functional Alterations between Normal and Alzheimer's Aging
长期跟踪正常衰老和阿尔茨海默病衰老之间的脑微血管结构和功能变化
基本信息
- 批准号:10265356
- 负责人:
- 金额:$ 36.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-30 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease related dementiaAmyloidAmyloid beta-ProteinAnimal HusbandryBehavioralBiological ModelsBiomedical EngineeringBlood VesselsBlood capillariesBlood flowCaregiversCause of DeathCerebrumClinical ResearchComputer ModelsConsensusCorrelation StudiesDataDefectDementiaDevelopmentDiagnosisDietary InterventionDiseaseEarly DiagnosisEarly treatmentEconomic BurdenEpidemicEtiologyFailureFunctional disorderHyperemiaImageImaging technologyImpaired cognitionIndividualKnowledgeLaboratory AnimalsLeadLongevityMeasuresMedical HistoryMicrocirculationModelingMusNerve DegenerationNetwork-basedNeurodegenerative DisordersNeuronsNeurosciencesOptical Coherence TomographyOxygenPathogenesisPathologyPharmaceutical PreparationsPharmacologyPlayPopulationProcessPropertyPublic HealthResearch Project GrantsResolutionRisk FactorsRoleSenile PlaquesStructural defectStructureSystemTechniquesTechnologyTestingThree-Dimensional ImageTimeUnited Statesabeta accumulationage relatedbasecerebral microvasculatureclinically relevantcomorbiditycomputer frameworkcostexercise interventiongene therapyhuman old age (65+)hypoperfusionimage processingimaging biomarkerimprovedin vivoin vivo imaginginsightinterestmouse modelneuron lossneurovascular couplingnew technologynormal agingpsychologicresponsesimulationsocialtherapeutic targettoolvascular factor
项目摘要
SUMMARY
Alzheimer’s disease (AD), a progressive neurodegenerative disorder affecting millions of people
worldwide, is currently incurable. As the population ages, AD and related dementia are becoming the biggest
epidemic in medical history: the number of people aged 65 and older with AD is projected to increase between
two- and three-fold by 2050. As shown by imaging and biomarker studies, age is a major risk factor for
developing dementia, and the pathophysiological processes of AD begin more than a decade before the
diagnosis of dementia. However, AD is a heterogeneous and multifactorial disease; thus, it is challenging to
fully understand how the multiple etiologies and age-related prodromal processes contribute to its
pathophysiology. Among other factors, deficits in cerebral microvascular structures and functions may play a
key role in the onset and development of AD. Despite its importance for early diagnosis and as a therapeutic
target, it is still unclear whether they are a causal factor for AD pathogenesis or an early consequence of
multifactorial conditions that lead to AD at a later stage. Especially, two critical knowledge gaps exist: (1)
Temporal relationships between vascular and other key factors during the onset and development of AD are
not clear; (2) Little has been studied about how individual defects in various microvascular structural and
functional properties distinctly correlate with and/or contribute to neuronal degeneration.
Here, we will develop, optimize, and integrate experimental and computational technologies for the
lifespan tracking and analysis of progressive microvascular alterations in AD versus normal aging in model
mice. First, we will optimize our optical coherence tomography imaging and 3D image processing techniques
to track the time-course of 32 vascular and non-vascular measures longitudinally over the mouse’s lifespan,
including microvascular structure, microcirculation, functional reactivity, Aβ plaque accumulation, neuronal
loss, and cognitive decline (Aim 1). These unprecedentedly comprehensive temporal dynamics data and
advanced statistical/correlation analyses will enable us to determine whether the microvascular deficits
precede neuronal loss or Aβ accumulation, and how those alterations are correlated, directly addressing the
first knowledge gap. In Aim 2, we will improve our computational model of microvascular flow and functional
hyperemia, and then combine the model with the experimental data of Aim 1 to investigate complicated cause-
effect relationships. Our computational model will enable us to essentially “turn on” and “turn off” each
microvascular deficit (e.g., thinner vessels, tortuous capillaries, hypoperfusion, capillary stalling) and test its
effect on oxygen delivery to neurons, which is difficult and sometimes impossible to achieve experimentally.
This combined approach will provide a powerful and unique strategy for testing the role of vascular deficits in
neuronal degeneration, directly addressing the second knowledge gap, and informing future research for
diagnosis and therapeutic target development.
摘要
阿尔茨海默病(AD),一种影响数百万人的进行性神经退行性疾病
在世界范围内,目前是无法治愈的。随着人口老龄化,阿尔茨海默病和相关的痴呆症正在成为最大的
医学史上的流行病:65岁及以上患有阿尔茨海默病的人数预计将在
到2050年,这个数字将翻两番和三倍。成像和生物标记物研究表明,年龄是患高血压的主要危险因素
发展为痴呆症,AD的病理生理过程早在十多年前就开始了
痴呆症的诊断。然而,阿尔茨海默病是一种异质性和多因素的疾病;因此,它具有挑战性
充分了解多种病因和与年龄相关的前驱过程是如何导致其
病理生理学。在其他因素中,脑微血管结构和功能的缺陷可能起到
在阿尔茨海默病的发生和发展中起关键作用。尽管它对早期诊断和治疗很重要
靶点,目前仍不清楚它们是AD发病的原因因素还是AD的早期后果
在以后阶段导致AD的多种因素。特别是,存在两个关键的知识缺口:(1)
在AD的发生和发展中,血管和其他关键因素之间的时间关系是
不清楚;(2)很少有人研究个体缺陷如何在各种微血管结构和
功能特性明显地与神经元变性相关和/或促成神经元退化。
在这里,我们将开发、优化和集成实验和计算技术
阿尔茨海默病与正常衰老模型中进行性微血管改变的寿命跟踪和分析
老鼠。首先,我们将优化我们的光学相干层析成像和3D图像处理技术
为了纵向跟踪小鼠寿命中32项血管和非血管措施的时间进程,
包括微血管结构、微循环、功能反应性、Aβ斑块堆积、神经元
失落和认知衰退(目标1)。这些空前全面的时间动力学数据和
先进的统计/相关分析将使我们能够确定微血管缺陷
在神经元丢失或β积聚之前,以及这些变化是如何相关的,直接解决
第一,知识鸿沟。在目标2中,我们将改进我们的微血管流动和功能的计算模型
充血,然后结合模型和目标1的实验数据来研究复杂的原因--
影响人际关系。我们的计算模型将使我们能够基本上“打开”和“关闭”每一个
微血管缺陷(例如,血管变细、毛细血管扭曲、低灌注度、毛细血管停滞),并测试其
对向神经元输送氧气的影响,这在实验上是困难的,有时是不可能实现的。
这种结合的方法将提供一种强大而独特的策略来测试血管缺陷在
神经元退化,直接解决第二个知识缺口,并为未来的研究提供信息
诊断和治疗靶点的开发。
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)
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Jonghwan Lee其他文献
Jonghwan Lee的其他文献
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{{ truncateString('Jonghwan Lee', 18)}}的其他基金
Label-Free, Longitudinal, Multi-Metric Viability Imaging of 3D Tissue Spheroid Array
3D 组织球体阵列的无标记、纵向、多指标活力成像
- 批准号:
10448442 - 财政年份:2021
- 资助金额:
$ 36.83万 - 项目类别:
Label-Free, Longitudinal, Multi-Metric Viability Imaging of 3D Tissue Spheroid Array
3D 组织球体阵列的无标记、纵向、多指标活力成像
- 批准号:
10665630 - 财政年份:2021
- 资助金额:
$ 36.83万 - 项目类别:
Label-Free, Longitudinal, Multi-Metric Viability Imaging of 3D Tissue Spheroid Array
3D 组织球体阵列的无标记、纵向、多指标活力成像
- 批准号:
10295612 - 财政年份:2021
- 资助金额:
$ 36.83万 - 项目类别:
Long-Term Tracking of Cerebral Microvascular Structural and Functional Alterations between Normal and Alzheimer's Aging
长期跟踪正常衰老和阿尔茨海默病衰老之间的脑微血管结构和功能变化
- 批准号:
10414100 - 财政年份:2020
- 资助金额:
$ 36.83万 - 项目类别:
Long-Term Tracking of Cerebral Microvascular Structural and Functional Alterations between Normal and Alzheimer's Aging
长期跟踪正常衰老和阿尔茨海默病衰老之间的脑微血管结构和功能变化
- 批准号:
10613561 - 财政年份:2020
- 资助金额:
$ 36.83万 - 项目类别:
Microscopic imaging of neuro-capillary coupling in brain cortex
大脑皮层神经毛细血管耦合的显微成像
- 批准号:
9172247 - 财政年份:2015
- 资助金额:
$ 36.83万 - 项目类别:
Microscopic imaging of neuro-capillary coupling in brain cortex
大脑皮层神经毛细血管耦合的显微成像
- 批准号:
9187012 - 财政年份:2015
- 资助金额:
$ 36.83万 - 项目类别:
Microscopic imaging of neuro-capillary coupling in brain cortex
大脑皮层神经毛细血管耦合的显微成像
- 批准号:
8713992 - 财政年份:2013
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