胆固醇转运子ABCA1调控滤泡B淋巴细胞功能抑制动脉粥样硬化发展的机制研究
结题报告
批准号:
81970371
项目类别:
面上项目
资助金额:
55.0 万元
负责人:
赵颖
依托单位:
学科分类:
动脉粥样硬化与动脉硬化
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
赵颖
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中文摘要
动脉粥样硬化的发病机制复杂,缺乏理想的治疗药,亟需寻找全新的治疗靶点。尽管胆固醇转运子ABCA1具有抗动脉粥样硬化作用,但其作用的靶细胞和机制尚不清楚。我们制备了B细胞特异性的ABCA1敲除小鼠(BKO),在该小鼠上的前期研究提示滤泡B(FOB)细胞是骨髓源性ABCA1发挥抗动脉粥样硬化作用的靶细胞。因此,本研究拟比较BKO与对照小鼠的FOB细胞在活化、增殖与凋亡、分化和抗体释放等功能上的差异,明确ABCA1调控FOB细胞功能的胆固醇依赖与非依赖性机制,并将FOB细胞过继转移入免疫缺陷的动脉粥样硬化模型小鼠中来确证FOB细胞上ABCA1的抗动脉粥样硬化作用及机制。最后我们将验证ABCA1对人FOB细胞功能的调控作用,并探讨源于FOB的外周血B2细胞上ABCA1的表达与冠心病发病间的相关性。本研究旨在通过对ABCA1抗动脉粥样硬化新机制的探讨,为临床治疗心血管疾病提供新的靶点与策略。
英文摘要
Atherosclerosis is a complex inflammatory disease with the involvement of many cell types and circulating mediators. Despite the extensive application of lipid lowering drugs, the high prevalence of myocardial infarction and stoke indicates an urgent need for the development/discovery of new therapeutic strategies/targets. ABCA1, a cholesterol transporter, protects against atherosclerosis. However, the effector cells and mechanisms underlying the atheroprotective effects of ABCA1 are still not clear,which greatly hampers the novel ABCA1-based therapeutic strategy for atherosclerosis. Previously, we generated B-cell specific ABCA1 knockout mice (BKO), and our studies on these mice indicated that follicular B (FOB) cells are effector cells responsible for atheroprotective effects of bone marrow-derived ABCA1. Therefore, in this proposal, we will, by using BKO and control mice, determine the effects of ABCA1 deficiency on the activation, proliferation, apoptosis, differentiation and antibody production of FOB cells. We will identify the cholesterol-related or -unrelated transcriptional factors/ signaling pathways underlying the regulation of FOB cells by ABCA1. Meanwhile, we will adoptively transfer of FOB cells, purified from BKO or control mice, into the B-cell deficient (uMT-/-) LDLr-/- mice to unambiguously illustrate the effects of FOB-derived ABCA1 on the development of atherosclerotic lesions. The possible involvement of T cells or IL-6 in this process will be determined by adoptive transfer of BKO/control FOB cells into Rag2-/-LDLr-/- recipients lacking both mature T and B cells, or transfer of IL-6-/-ABCA1-/-/IL-6-/-ABCA1+/+ FOB cells into uMT-/-LDLr-/- mice, respectively. Finally, we will analyze the functions of ABCA1 on human FOB cells, and compare ABCA1 expression on circulating B2 cells mainly derived from FOB, their cholesterol efflux capacities as well as phenotype/functions of B2 cells between healthy controls and patients of coronary heart diseases (CHD) to figure out the possible relationship among ABCA1 expression/function, phenotypes of B2 cells and the incidence of CHD. The proposed study will unravel novel mechanisms responsible for the atheroprotection of ABCA1 and may discover novel potential therapeutic targets for atherosclerosis.
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专利列表
DOI:10.3389/fphar.2021.679707
发表时间:2021
期刊:Frontiers in pharmacology
影响因子:5.6
作者:Li H;Du S;Niu P;Gu X;Wang J;Zhao Y
通讯作者:Zhao Y
DOI:--
发表时间:2022
期刊:中国动脉硬化杂志
影响因子:--
作者:丁芳芳;杨燕;刘立民;赵颖
通讯作者:赵颖
DOI:10.1161/ATVBAHA.122.318226
发表时间:2022
期刊:Arteriosclerosis, Thrombosis, and Vascular Biology
影响因子:--
作者:Ying Zhao;Lili Zhang;Limin Liu;Xuan Zhou;Fangfang Ding;Yan Yang;Shiyu Du;Hongmin Wang;Miranda Van Eck;Jun Wang
通讯作者:Jun Wang
DOI:10.3389/fimmu.2021.713294
发表时间:2021
期刊:Frontiers in immunology
影响因子:7.3
作者:Cheng ZY;He TT;Gao XM;Zhao Y;Wang J
通讯作者:Wang J
Altered Phenotype and Enhanced Antibody-Producing Ability of Peripheral B Cells in Mice with Cd19-Driven Cre Expression.
通过CD19驱动的CRE表达的小鼠外周B细胞的表型改变和增强的抗体产生能力。
DOI:10.3390/cells11040700
发表时间:2022-02-16
期刊:Cells
影响因子:6
作者:Zhao Y;Zhao S;Qin XY;He TT;Hu MM;Gong Z;Wang HM;Gong FY;Gao XM;Wang J
通讯作者:Wang J
胆固醇主动流出机制对CD4+ T细胞功能的影响及其机制研究
  • 批准号:
    31400768
  • 项目类别:
    青年科学基金项目
  • 资助金额:
    25.0万元
  • 批准年份:
    2014
  • 负责人:
    赵颖
  • 依托单位:
胆固醇转运子ABCA1调控CD4+T细胞免疫应答抑制动脉粥样硬化的新机制研究
  • 批准号:
    81470564
  • 项目类别:
    面上项目
  • 资助金额:
    73.0万元
  • 批准年份:
    2014
  • 负责人:
    赵颖
  • 依托单位:
国内基金
海外基金