Development of Rac-Targeted Therapeutic Strategy for Treatment of Calcific Atherosclerosis

钙化动脉粥样硬化 Rac 靶向治疗策略的开发

基本信息

项目摘要

PROJECT SUMMARY/ABSTRACT: Coronary artery disease (CAD) from calcific atherosclerosis is the single leading cause of morbidity and mortality worldwide. The calcium composition of atherosclerotic plaque has predictive value in terms of cardiovascular events. Inflammation is likely a key mediator of vascular calcification, but immune signaling mechanisms that promote this process are minimally understood. Recently, the small GTPase, Rac2, was identified as a major inflammatory regulator of signaling that directs plaque osteogenesis. Atherosclerotic aortas from ApoE-/- mice fed a high fat diet supplemented with cholesterol demonstrated dynamic expression of Rac2 mRNA expression over time. Moreover, decreased Rac2 expression correlated with increased atherosclerotic calcification, both in the experimental animal model and in human coronary artery plaques. Rac2 -/-ApoE -/- mice helped to define a protective role of Rac2, which prevented progressive calcification through its suppression of Rac1-dependent macrophage IL-1β expression. Plaque and serum from mice with calcified plaque demonstrated increased expression of IL-1β, and moreover, treatment with the IL-1 receptor antagonist inhibited the enhanced atherosclerotic calcification. IL-1β expression was a key driver of vascular smooth muscle cell calcium deposition by its ability to promote osteogenic transcriptional programs, including expression of the osteogenic transcription factors, RUNX2, SOX9, OSX and MSX2. Bone marrow transplantation confirmed the progressive calcification of plaque attributable to Rac2 gene deletion was dependent on the hematopoietic compartment. Several key questions remain: 1) what is the role of macrophage Rac1 in plaque development and atherosclerotic calcification in standard experimental models; 2) are macrophages the key cellular source of plaque IL-1β; 3) how does Rac2 suppress Rac1-dependent macrophage IL-1β expression; and 4) are these signaling mechanisms relevant to calcified atherosclerotic plaque from patients with coronary artery disease? The overall objective of the proposed studies is to thoroughly answer these questions. Preliminary data demonstrate that Rac1 can be a key promoter of macrophage IL-1β expression and that Rac2 and Rac1 may antagonize each other through competition for a similar guanine nucleotide exchange factor, Tiam1, which is upregulated under conditions that activate IL-1β expression. The hypothesis is that macrophage Rac signaling determines atherosclerotic plaque IL-1β expression and consequent inflammatory atherosclerotic calcification, and thus disrupting this pathway can be an effective strategy for the prevention and treatment of CAD. Aim1 will define the role of macrophage Rac1 in plaque IL-1β expression and atherosclerotic calcification. Aim2 will confirm that Rac1 and Rac2 compete for Tiam1, a critical Rac-GEf that is upregulated during macrophage inflammatory activation as well as during experimental atherosclerosis, and that IL-1β expression and inflammatory atherosclerotic calcification are dependent on Tiam1 expression. Finally, Aim3 will confirm the validity of these macrophage signaling mechanisms in atherosclerotic plaque samples from patients with known coronary artery disease. Confirming that a macrophage Rac-IL-1β signaling axis is a central mechanism in inflammatory atherosclerotic calcification paves the way for developing a novel therapeutic strategy for treating coronary artery disease, as small molecular inhibitors of Rac1 and Rac1-Tiam1 interactions have been developed and are incorporated into a number of the proposed studies.
项目总结/文摘:

项目成果

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Alan Ross Morrison其他文献

Alan Ross Morrison的其他文献

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{{ truncateString('Alan Ross Morrison', 18)}}的其他基金

Combining Targeted Demethylation with Noncoding RNA-mediated mRNA Stabilization as a Strategy for Therapeutic Arteriogenesis in the Aged
将靶向去甲基化与非编码 RNA 介导的 mRNA 稳定相结合作为治疗老年人动脉生成的策略
  • 批准号:
    10826740
  • 财政年份:
    2022
  • 资助金额:
    $ 37.67万
  • 项目类别:
Combining Targeted Demethylation with Noncoding RNA-mediated mRNA Stabilization as a Strategy for Therapeutic Arteriogenesis in the Aged
将靶向去甲基化与非编码 RNA 介导的 mRNA 稳定相结合作为治疗老年人动脉生成的策略
  • 批准号:
    10597229
  • 财政年份:
    2022
  • 资助金额:
    $ 37.67万
  • 项目类别:
Combining Targeted Demethylation with Noncoding RNA-mediated mRNA Stabilization as a Strategy for Therapeutic Arteriogenesis in the Aged
将靶向去甲基化与非编码 RNA 介导的 mRNA 稳定相结合作为治疗老年人动脉生成的策略
  • 批准号:
    10631563
  • 财政年份:
    2022
  • 资助金额:
    $ 37.67万
  • 项目类别:
Reprogramming Macrophages to Improve Vascular Healing in Diabetes
重编程巨噬细胞以改善糖尿病血管愈合
  • 批准号:
    10260749
  • 财政年份:
    2021
  • 资助金额:
    $ 37.67万
  • 项目类别:
Reprogramming Macrophages to Improve Vascular Healing in Diabetes
重编程巨噬细胞以改善糖尿病血管愈合
  • 批准号:
    10426222
  • 财政年份:
    2021
  • 资助金额:
    $ 37.67万
  • 项目类别:
Reprogramming Macrophages to Improve Vascular Healing in Diabetes
重编程巨噬细胞以改善糖尿病血管愈合
  • 批准号:
    10674353
  • 财政年份:
    2021
  • 资助金额:
    $ 37.67万
  • 项目类别:
Reprogramming Macrophages to Improve Vascular Healing in Diabetes
重编程巨噬细胞以改善糖尿病血管愈合
  • 批准号:
    10709502
  • 财政年份:
    2021
  • 资助金额:
    $ 37.67万
  • 项目类别:
Development of Rac-Targeted Therapeutic Strategy for Treatment of Calcific Atherosclerosis
钙化动脉粥样硬化 Rac 靶向治疗策略的开发
  • 批准号:
    10304197
  • 财政年份:
    2018
  • 资助金额:
    $ 37.67万
  • 项目类别:
Development of Rac-Targeted Therapeutic Strategy for Treatment of Calcific Atherosclerosis
钙化动脉粥样硬化 Rac 靶向治疗策略的开发
  • 批准号:
    10531676
  • 财政年份:
    2018
  • 资助金额:
    $ 37.67万
  • 项目类别:
Calcific Atherosclerosis is Mediated by Macrophage Adhesion Signaling
钙化动脉粥样硬化是由巨噬细胞粘附信号介导的
  • 批准号:
    8733374
  • 财政年份:
    2014
  • 资助金额:
    $ 37.67万
  • 项目类别:

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