Role of CD13 and its activators in vascular inflammation

CD13及其激活剂在血管炎症中的作用

基本信息

批准号：
8379841
负责人：
LINDA H SHAPIRO
金额：
$ 38.1万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8379841
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 homing macrophage mast cell migration monocyte monolayer novel protective effect release of sequestered calcium ion into cytoplasm response sialic acid binding Ig-like lectin vascular inflammation

项目摘要

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.

CD13/氨肽酶 N 细胞表面肽酶表达于活化的内皮细胞和正常细胞上。骨髓系细胞，包括单核细胞、粒细胞、巨噬细胞、树突状细胞和肥大细胞。我们发现单核细胞或内皮细胞与 CD13 激活单克隆抗体发生交联以信号转导依赖性方式显着增强细胞与细胞的粘附，与模仿天然 CD13 激活剂的抗体，可调节细胞粘附。一致同意，虽然他们的造血功能正常，CD13 缺失小鼠的巨噬细胞能力明显受损粘附于单层内皮细胞，表明 CD13 参与炎症单核细胞/内皮细胞互动。此外，缺乏 CD13 的小鼠在多发性硬化症模型中受到完全保护，强烈暗示在炎症自身免疫机制中也发挥着关键作用。调查相关分子机制表明，可溶性重组CD13可阻断这种粘附，激活单核细胞粘附于固定化重组 CD13，单核细胞和内皮细胞 CD13 均在单一免疫复合物中发现，表明 CD13 直接参与粘附。此外，粘附严格依赖于唾液酸部分，暗示唾液酸结合蛋白的作用 CD13 粘附中的 DSiglecsD。鉴定 CD13 激活剂的生理来源，即小鼠血清发生过敏反应或动脉粥样硬化，但其他炎症损伤不会增加 CDIS 依赖的单核细胞/内皮粘附，因此我们可以从蛋白质组学上识别这一有趣的现象 CDIS 特异性炎症调节因子，决定响应特定的细胞间相互作用挑战。总的来说，这些数据支持 CD13 作为分子界面的作用，可诱导和参与关键的炎症细胞相互作用，并可能提供有关高水平炎症细胞的见解血清唾液酸与心血管疾病相关。实验计划将剖析相关的使用条件 CD13 缺失动物体内单核细胞 CD13 对炎症过程的贡献炎症模型。此外，我们将确定 CD13 的新分子机制相关性（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、类风湿性关节炎和癌症。在这些疾病中，通常的保护机制会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。