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Heparan sulfate proteoglycan in the brain vascular clearance of amyloid-β and Alzheimer's disease

Heparan sulfate proteoglycan in the brain vascular clearance of amyloid-β and Alzheimer's disease
硫酸乙酰肝素蛋白多糖在脑血管清除淀粉样蛋白-β 和阿尔茨海默氏病中的作用
批准号:
10301892
负责人:
Lianchun Wang
金额:
$179.38万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-08-15 至 2024-07-31

项目摘要

项目成果

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中文摘要
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项目总结
英文摘要
PROJECT SUMMARY Alzheimer`s disease (AD) is a progressive degenerative disease of the brain, a dementing illness associated with early neurovascular changes and the accumulation of misfolded amyloid-β (Aβ) and tau in the brain. At present, no effective treatment is available to slow or halt the progression of AD. Hence, uncovering novel mechanisms that govern AD pathogenesis may advance the development of more effective therapeutic strategies to treat this devastating disease. Mounting evidence suggests that the accumulation and aggregation of Ab in brain parenchyma and cerebral blood vessels (CBVs) is a key event leading to other AD-related pathologies. Kinetic studies in patients with sporadic AD indicate that faulty Aβ clearance, rather than Aβ overproduction, is critical for accumulation and aggregation of Aβ in brain. However, the molecular underpinnings of such Aβ accumulation remain poorly understood. Our preliminary studies indicate that heparan sulfate (HS), a type of sulfated polysaccharide that critically mediates cell-cell and cell-matrix interaction and signaling, is strongly reduced in CBVs of AD patients. In this application, we will test our novel hypothesis that HS expressed in CBVs normally facilitates the clearance of Ab out of the brain and that such function is disrupted in AD, leading to impaired Ab clearance. Mechanistically, we hypothesize that HS maintains CBV integrity, functions as a co-receptor in LRP1-mediated Ab clearance and facilitates perivascular Ab elimination. We will pursue the following 3 specific aims to rigorously test our hypothesis: 1. Elucidate the roles of brain endothelial cell (bEC) HS in Ab clearance and test the hypothesis that increasing bEC-HS expression normalizes Ab clearance to mitigate AD pathogenesis. 2. Delineate the molecular mechanisms underlying the roles of bEC-HS in brain Ab clearance and AD pathogenesis. 3. Elucidate the roles of brain vascular smooth muscle cell (bVSMC)- HS in brain Ab clearance and AD pathogenesis. These proposed studies exploit both novel and established genetic, cellular, scRNA-seq and biochemical approaches in conjunction with human AD specimen and AD mouse models. The results of this study are expected to illuminate HS expressed in CBVs serves as a key molecule to mediate brain Ab clearance and decreased CVS-HS expression exacerbates AD, and will provide in vivo evidence for the proof of principle that increasing bEC-HS is an effective intervention to mitigate AD pathogenesis.
期刊论文(8)
专著(0)
科研奖励(0)
会议论文
Application of a Mutant Cell Library to Determine the Structure-Function Relationship of Heparan Sulfate in Facilitating FGF2-FGFR1 Signaling.
应用突变细胞库确定硫酸乙酰肝素促进 FGF2-FGFR1 信号传导的结构功能关系。
DOI: 10.1007/978-1-0716-1398-6_48
发表时间: 2022
期刊: Methods in molecular biology (Clifton, N.J.)
影响因子: --
作者: [Faulkner,John, Song,Xuehong, Wang,Lianchun]
通讯作者: Wang,Lianchun
DOI: 10.1016/j.carbpol.2022.120176
发表时间: 2022-10-05
期刊: CARBOHYDRATE POLYMERS
影响因子: 11.2
作者: [Jin,Weihua, Lu,Chenghui, Zhang,Fuming]
通讯作者: Zhang,Fuming
DOI: 10.1007/s10719-021-10018-8
发表时间: 2022-06
期刊: Glycoconjugate journal
影响因子: 3
作者: [Zeng J, Meng Y, Chen SY, Zhao G, Wang L, Zhang EX, Qiu H]
通讯作者: Qiu H
DOI: 10.1007/s12017-020-08607-1
发表时间: 2020-12
期刊: Neuromolecular medicine
影响因子: 3.5
作者: [Garbuzova-Davis S, Willing AE, Ehrhart J, Wang L, Sanberg PR, Borlongan CV]
通讯作者: Borlongan CV
6
    Using CRISPR-Cas9 technology to develop a mutant cell library for heparan sulfate structure-function study
    • 批准号:
      8985421
    • 项目类别:
    • 资助金额:
      $29.1万
    • 财政年份:
      2015
    • 负责人:
      Lianchun Wang
    • 依托单位:
    MOLECULAR MECHANISMS UNDERLYING HEPARIN-INDUCED LEUKOCYTOSIS
    • 批准号:
      8361868
    • 项目类别:
    • 资助金额:
      $0.18万
    • 财政年份:
      2011
    • 负责人:
      Lianchun Wang
    • 依托单位:
    ROLE OF ENDOTHELIUM ON MYOCARDIAL INFARCTION INJURY RESPONSE
    • 批准号:
      8361867
    • 项目类别:
    • 资助金额:
      $0.18万
    • 财政年份:
      2011
    • 负责人:
      Lianchun Wang
    • 依托单位:
    REGULATORY MECHANISM OF HEPARIN/HEPARAN SULFATE ON VEGF SIGNALING
    • 批准号:
      8361866
    • 项目类别:
    • 资助金额:
      $0.18万
    • 财政年份:
      2011
    • 负责人:
      Lianchun Wang
    • 依托单位: