Proteomics based mapping of cardiac extracellular matrix to define sex and age-dependent changes

基于蛋白质组学的心脏细胞外基质图谱来定义性别和年龄依赖性变化

基本信息

  • 批准号:
    10751473
  • 负责人:
  • 金额:
    $ 60.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-08-01 至 2028-04-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY The extracellular matrix (ECM) provides a scaffold for cardiac structural integrity and plays an active role in modulating cellular responses. ECM consists of a network of fibrillar proteins and proteoglycans binding cyto- kines, growth factors, and ECM-modifying enzymes. The aging heart develops interstitial fibrosis, and prelimi- nary data demonstrate that different proteins are enriched in ECM in the male and female heart. An altered ECM can affect cellular phenotypes. The ECM-cell communication occurs via cell surface receptors such as integrins, through outside-in signaling, where integrin-binding to ECM protein domains translates into prolifera- tion, differentiation, or gene expression. On the other hand, activation of the intracellular integrin tail increases their ECM-binding affinity, promoting adhesion, migration, or ECM assembly (by inside-out signaling). There- fore, ECM dictates a cellular phenotype, but cells can modify ECM in response by changing its composition or assembly. Because of profound differences in ECM composition in males and females, we hypothesize that the quality of repair assembled after injury and subsequent adverse remodeling in males and females will also be differ- ent, and the differences will be accentuated by aging. In SA1, we will map the differences in ECM dependent on age (young and old animals will be studied), sex hormone level (animals will be subjected to chemical ovary failure or castration) or level of inflammation (CCL2KO animals will be used; these mice have reduced leuko- cyte infiltration and therefore reduced fibrosis). The cellular phenotype of fibroblasts, endothelial cells (ECs), and smooth muscle cells (SMCs) isolated from all these animals will be studied ex vivo and in 3D culture. The effect of ECM on cell phenotype will be tested in 3D cultures using the matrix swap approach, where i.e. young cells will be cultured on ECM from the old hearts and vice versa. And the effect of matrix stiffness on the pro- duction of ECM protein will be examined as well. Similarly, the physiology of human cells will be studied. In SA2, we will examine ECM-integrin dependent phenotypic changes in mouse and human cells. We will first examine the effect of sex hormones, age, and inflammation on the levels of integrin expression in fibroblasts, ECs, and SMCs. Then we will manipulate the integrin expression level (via downregulation or overexpression), and examine the cellular phenotype. Finally, we will manipulate estrogen and androgen receptors and deter- mine the effect of these manipulations on integrin levels and ECM protein synthesis. In SA3, we will examine how sex hormone levels and age affect scar formation and adverse remodeling after ischemia/reperfusion inju- ry. Changes in ECM will be examined via ELISA, mass spectrometry, and western blot. The approach is inno- vative because it examines the role of three superimposed variables (age, sex hormone, and inflammation) on ECM and cellular phenotypes. Successful completion of these studies will provide a mechanistic link for future therapeutics targeting insufficient reparative and excessive adverse fibrosis.
项目总结 细胞外基质(ECM)为心脏结构完整性提供了支架,并在 调节细胞反应。细胞外基质由纤维蛋白和结合细胞的蛋白多糖网络组成。 动素、生长因子和细胞外基质修饰酶。老化的心脏会发展成间质纤维化,初步- 没有数据表明,在男性和女性心脏中,ECM中富含不同的蛋白质。更改后的 细胞外基质可以影响细胞表型。细胞外基质与细胞间的通讯是通过细胞表面受体实现的,如 整合素,通过外向内信号,其中整合素与ECM蛋白结构域结合转化为增殖- 分化,分化或基因表达。另一方面,细胞内整合素尾巴的激活增加 它们的ECM结合亲和力,促进黏附、迁移或ECM组装(通过由内向外的信号)。在那里- 因此,细胞外基质决定细胞的表型,但细胞可以通过改变其组成或改变其反应来修改细胞外基质 集合。由于男性和女性在细胞外基质成分上的巨大差异,我们假设 男性和女性在受伤后组装的修复质量和随后的不良重塑也将有所不同- 而且随着年龄的增长,这种差异会更加明显。在SA1中,我们将映射ECM依赖于 年龄(幼年和老年动物将被研究),性激素水平(动物将受到化学卵巢的影响 失败或阉割)或炎症程度(将使用CCL2KO动物;这些小鼠已降低白细胞- 细胞渗出,从而减少纤维化)。成纤维细胞、内皮细胞、 从所有这些动物中分离的平滑肌细胞(SMC)将在体外和3D培养中进行研究。这个 细胞外基质对细胞表型的影响将在3D培养中使用基质交换方法进行测试,其中 细胞将在来自旧心脏的ECM上培养,反之亦然。并分析了基质刚度对材料性能的影响。 ECM蛋白的诱导也将被检测。类似地,我们将研究人类细胞的生理学。在……里面 SA2,我们将检测依赖于ECM整合素的小鼠和人类细胞的表型变化。我们将首先 检测性激素、年龄和炎症对成纤维细胞整合素表达水平的影响, ECS和SMCS。然后我们将操纵整合素的表达水平(通过下调或过度表达), 并检查细胞表型。最后,我们将操纵雌激素和雄激素受体,阻止- 挖掘这些操作对整合素水平和细胞外基质蛋白质合成的影响。在SA3中,我们将检查 性激素水平和年龄对缺血/再灌注损伤后瘢痕形成和不良重塑的影响 瑞。细胞外基质的变化将通过酶联免疫吸附试验、质谱学和蛋白质印迹法进行检测。这种方法是不可能的- Vative,因为它检查了三个叠加变量(年龄、性激素和炎症)在 细胞外基质和细胞表型。这些研究的成功完成将为今后的工作提供机制上的联系 针对修复不足和过度不良纤维化的治疗。

项目成果

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KATARZYNA A. CIESLIK其他文献

KATARZYNA A. CIESLIK的其他文献

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{{ truncateString('KATARZYNA A. CIESLIK', 18)}}的其他基金

INTERACTION OF MESENCHYMAL AND MYELOID FIBROBLASTS IN INFLAMMATORY-BASED FIBROSIS IN THE AGING HEART
间充质和骨髓成纤维细胞在衰老心脏炎症性纤维化中的相互作用
  • 批准号:
    10611152
  • 财政年份:
    2018
  • 资助金额:
    $ 60.13万
  • 项目类别:
INTERACTION OF MESENCHYMAL AND MYELOID FIBROBLASTS IN INFLAMMATORY-BASED FIBROSIS IN THE AGING HEART
间充质和骨髓成纤维细胞在衰老心脏炎症性纤维化中的相互作用
  • 批准号:
    9790895
  • 财政年份:
    2018
  • 资助金额:
    $ 60.13万
  • 项目类别:
INTERACTION OF MESENCHYMAL AND MYELOID FIBROBLASTS IN INFLAMMATORY-BASED FIBROSIS IN THE AGING HEART
间充质和骨髓成纤维细胞在衰老心脏炎症性纤维化中的相互作用
  • 批准号:
    10188370
  • 财政年份:
    2018
  • 资助金额:
    $ 60.13万
  • 项目类别:
GLYCINE AND N-ACETYL CYSTEINE SUPPLEMENTED DIET IMPROVES INFLAMMATORY-BASED FIBROSIS IN THE AGING HEART
补充甘氨酸和 N-乙酰半胱氨酸的饮食可改善衰老心脏中的炎症性纤维化
  • 批准号:
    10284824
  • 财政年份:
    2018
  • 资助金额:
    $ 60.13万
  • 项目类别:

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