The Role of CD13 and its activators in vascular inflammation

CD13及其激活剂在血管炎症中的作用

• 批准号: 7662916
• 负责人: LINDA H SHAPIRO
• 金额: $ 39.42万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-26 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7662916
• 关键词: Acute; Adhesions; Affect; Agreement; Animals; Antibodies; Architecture; Atherosclerosis; Autoimmune Process; Binding Proteins; Carbohydrates; Cardiovascular Diseases; Cell Adhesion; Cell Adhesion Molecules; Cell Communication; Cell surface; Cell-Cell Adhesion; Cells; Complex; DNA Sequence Rearrangement; Data; Diabetes Mellitus; Disease; Disease model; Dissection; E-Selectin; Employee Strikes; Endothelial Cells; Endothelium; Enzymes; Experimental Autoimmune Encephalomyelitis; Goals; Hematopoietic; Hypersensitivity; Immune; Immune response; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Instruction; Investigation; Knock-out; Knockout Mice; Lead; Leukocyte Trafficking; Ligation; Link; Malignant Neoplasms; Mediating; Modeling; Modification; Molecular; Monoclonal Antibodies; Multiple Sclerosis; Mus; Myelogenous; Normal Cell; Peptide Hydrolases; Peritonitis; Phenotype; Physiological; Play; Post-Translational Protein Processing; Process; Production; Protein Tyrosine Kinase; Reaction; Recombinants; Relative (related person); Rheumatoid Arthritis; Role; Serum; Sialic Acids; Signal Transduction; Site; Source; Therapeutic; Tissues; alanine aminopeptidase; base; crosslink; cytokine; granulocyte; human disease; in vivo; in vivo Model; insight; leukocyte activation; leukocyte homing; macrophage; mast cell; migration; monocyte; monolayer; novel; protective effect; release of sequestered calcium ion into cytoplasm; response; vascular inflammation

The CD13/aminopeptidase N cell surface peptidase is expressed on activated endothelial cells and normal cells of the myeloid lineage including monocytes, granulocytes, macrophages dendritic, and mast cells. We find that crosslinking of either monocytes or endothelial cells with activating monoclonal antibodies to CD13 significantly enhances cell-cell adhesion in a signal transduction dependent manner consistent with the antibody mimicking a natural CD13 activator that regulates cell adhesion. In agreement, while their hematopoietic profiles are normal, macrophages from CD13 null mice are significantly impaired in their ability to adhere to endothelial monolayers, suggesting CD13 participates in inflammatory monocyte/endothelial interactions. In addition, mice lacking CD13 are completely protected in a model of multiple sclerosis, strongly implicating a critical role in inflammatory autoimmune mechanisms as well. Investigation into the relevant molecular mechanisms showed that soluble recombinant CD13 blocks this adhesion, activated monocytes adhere to immobilized recombinant CD13 and both monocyte and endothelial cell CD13 are found in a single immunocomplex, suggesting that CD13 directly participates in the adhesion. Furthermore, adhesion is strictly dependent on sialyl moieties, implicating a role for the sialic acid binding proteins DSiglecsD in CD13 adhesion. To identify a physiologic source of the CD13 activator, serum from mice undergoing hypersensitivity reactions or atherosclerosis but not other inflammatory insults increases CDIS-dependent monocyte/endothelial adhesion, thus we can proteomically identify this intriguing CDIS-specific inflammatory regulator that dictates novel cell-cell interactions in response to specific challenges. Collectively, these data support a role for CD13 as a molecular interface that induces and participates in critical inflammatory cell interactions and may provide insights regarding the high levels of serum sialic acid associated with cardiovascular disease. The experimental plan will dissect the relative contribution of monocytic CD13 to inflammatory processes using conditional CD13 null animals in in vivo models of inflammation. In addition, we will identify the novel molecular mechanisms by which CD13 RELEVANCE (See instructions): Inflammation is linked to the progression of many human diseases such as cardiovascular disease, diabetes, rheumatoid arthritis, and cancer. In these diseases normally protective mechanisms become unbalanced and lead to tissue damage and intensification of disease. Understanding the molecules and mechanisms that regulate normal functions is critical to controlling their dysregulation in disease.

CD 13/氨基肽酶N细胞表面肽酶在活化的内皮细胞和正常的 髓系细胞，包括单核细胞、粒细胞、巨噬细胞、树突细胞和肥大细胞。我们 发现单核细胞或内皮细胞与活化的CD 13单克隆抗体的交联 显著增强细胞-细胞粘附的信号转导依赖的方式与 模拟调节细胞粘附的天然CD 13激活剂的抗体。在协议中， 造血特征正常，来自CD 13缺失小鼠的巨噬细胞的造血能力显著受损， 粘附到内皮细胞单层，表明CD 13参与炎症单核细胞/内皮细胞 交互.此外，缺乏CD 13的小鼠在多发性硬化症模型中得到完全保护， 这也强烈暗示了在炎症性自身免疫机制中的关键作用。调查 相关的分子机制表明，可溶性重组CD 13阻断这种粘附，激活 单核细胞粘附于固定化的重组CD 13，单核细胞和内皮细胞CD 13均 发现在一个单一的免疫复合物，表明CD 13直接参与粘附。此外，委员会认为， 粘附严格依赖于唾液酸部分，暗示唾液酸结合蛋白的作用 CD 13粘附中的DSiglecsD。为了鉴定CD 13激活剂的生理来源，来自小鼠的血清 发生超敏反应或动脉粥样硬化而非其他炎症性损伤时， CDIS依赖的单核细胞/内皮细胞粘附，因此我们可以从蛋白质组学上鉴定这种有趣的 CDIS特异性炎症调节因子，其决定了响应特异性CDIS的新型细胞-细胞相互作用。 挑战总的来说，这些数据支持CD 13作为分子界面的作用， 参与关键的炎症细胞相互作用，并可能提供有关高水平的 血清唾液酸与心血管疾病相关。实验计划将解剖相对 使用条件性CD 13缺失动物体内研究单核细胞CD 13对炎症过程的贡献 炎症模型。此外，我们将确定新的分子机制，CD 13 相关性（参见说明）： 炎症与许多人类疾病的进展有关，例如心血管疾病，糖尿病， 风湿性关节炎和癌症。在这些疾病中，通常保护机制变得不平衡 并导致组织损伤和疾病加剧。了解分子和机制 调节正常功能对于控制疾病中的失调至关重要。