Recognition of Fibrinogen by Leukocyte Integrins

白细胞整合素对纤维蛋白原的识别

• 批准号: 8039061
• 负责人: Tatiana P Ugarova
• 金额: $ 38.13万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8039061
• 关键词: Adhesiveness; Adhesives; Affect; Amino Acids; Animal Model; Anti-Bacterial Agents; Atherosclerosis; Binding; Biological; Biology; Blood Circulation; CAP18 lipopolysaccharide-binding protein; Cardiovascular Diseases; Cell Surface Receptors; Cells; Characteristics; Consensus; Cytoplasmic Granules; Data; Disease; Emigrations; Endothelium; Exhibits; Family; Fibrinogen; Funding; Goals; Host Defense; Human; ITGAM gene; ITGB2 gene; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Integrins; Knowledge; Lead; Leukocytes; Ligand Binding; Ligands; Lymphatic; Macrophage-1 Antigen; Mass Spectrum Analysis; Mediating; Methods; Modeling; Molecular; Mus; Pathogenesis; Peptide Library; Peptides; Play; Post-Translational Protein Processing; Process; Property; Protein Databases; Proteins; Reaction; Resolution; Rheumatoid Arthritis; Role; Signal Transduction; Site; Specificity; Surface; Testing; Translating; Up-Regulation; adhesion receptor; base; cathelicidin; combinatorial; design; in vivo; insight; macrophage; member; migration; monocyte; neutrophil; neutrophil basic protein; novel therapeutics; prototype; receptor; response; restenosis; therapeutic target

DESCRIPTION (provided by applicant): Leukocyte integrin aM¿2 (CD11b/CD18, Mac-1) plays a pivotal role in normal protective inflammatory response and pathological inflammation. This receptor has prodigious adhesive and signaling capabilities which allowed it to become the premier workhorse in host defense. It is also a potential therapeutic target in many diseases in which inflammation plays an essential role, including cardiovascular diseases. The diverse functions and activities ascribed to aM¿2 arise from its ability to bind a multitude of structurally diverse ligands. However, the mechanisms which allow aM¿2 to exhibit broad ligand recognition are still poorly understood. Our previous studies with a prototype a aM¿2 ligand fibrinogen provided initial insight into the mechanism by which the aMI-domain of the receptor recognizes its ligands. In the past funding period we have solved the consensus aMI-domain recognition motif, we termed IRM. A key feature of IRM is a small core consisting of specific combinations of basic and hydrophobic amino acid residues ubiquitous in many aM¿2 ligands. The characteristics of IRM are consistent with the capacity of aM¿2 to recognize a wide variety of unrelated sequences and, thus, form a molecular basis for aM¿2 ligand binding promiscuity. Specific Aim1 is to further characterize the mechanism underlying broad recognition specificity of aM¿2. Combinatorial peptide libraries and mutational analyses will be used to clarify the structural features of IRM. Mass spectrometry will be used to determine the effect of inflammation-associated protein modifications on the function of IRM. Our preliminary studies revealed that neutrophil secretion products are enriched in IRMs which allowed their prediction as a new class of aM¿2 ligands. We have found that one of them, human neutrophil cathelicidin peptide LL-37, effectively binds aMb2 and induces a potent aM¿2- dependent migratory response. Based on this finding we propose that LL-37 and other neutrophil-derived proteins/peptides exert their potent immunomodulatory effects by binding aM¿2 on monocyte/macrophages. Specific Aim 2 is to test this hypothesis by characterizing aM¿2-dependent monocyte responses elicited by LL-37. The effect of LL-37 on signaling and migratory functions of aM¿2 will be determined using aM¿2- expressing and aM¿2-deficient cells and in the in vivo animal model. Studies over the past funding period identified integrin aD¿2 as a multi-ligand receptor with specificity similar to that of aM¿2 and revealed that its upregulation on inflammatory macrophages inhibits their migration. Specific Aim 3 is to characterize the role of aM¿2 and aD¿2, two most abundant and adhesive integrins on macrophages, in emigration of these cells from the inflammatory site during the resolution of inflammation. The efflux of macrophages by draining lymphatics will be investigated in wild-type and integrin-deficient mice. Overall, these studies will lead to an increased understanding of the principles which govern ligand recognition by aM¿2, will give new insights into the biology of aM¿2 and aD¿2 and may be useful in the design of novel therapeutic strategies. PUBLIC HEALTH RELEVANCE: Inflammation is critically involved in the pathogenesis of many disorders, including cardiovascular disease. Integrin aM¿2 (Mac-1) is the most versatile receptor on leukocytes and mediates numerous responses of these cells during the inflammatory response. The multiplicity of functions exhibited by Mac-1 depends on its ability to bind a myriad of diverse proteins. Understanding the molecular basis for the extreme stickiness of Mac-1 and the biological significance of receptor's broad recognition could lead to new methods of treatment of disorders in which inflammation plays a role.

描述（由申请人提供）：白细胞整合素2（CD11b/CD18，MAC-1）在炎症和病理炎症的炎症和信号能力中起着关键作用。功能和活动2来自结合多种结构多样的配体的能力。 2表现出广泛的配体识别仍然知之甚少。 2配体纤维蛋白原被识别为识别的AMI域是e的。酸残基无处不在2配体。 2识别多种未实现的序列，因此构成了AM的分子基础2配体结合放射线。 2。组合肽文库和突变分析将使IRM的结构特征确定炎症蛋白质修饰对IRM功能的影响。 2配体。 2-迁移反应。 2在单核细胞/巨噬细胞上。 LL-37引起的2依赖性单核细胞反应。 2将使用AM确定2-表达和在过去的融合素AD上，有2个缺陷的细胞和体内动物模型。 2作为具有类似于AM的特异性的多配体受体2并揭示了炎症性巨噬细胞的上调抑制了它们的迁移。 2和广告2，在野生型和整联蛋白缺乏的小鼠中，通过研究的排水消耗的两种最丰富和粘合剂整合素在巨噬细胞排出过程中。配体认可2，将为AM的生物学提供新的见解2和广告2，并且在新型治疗策略的设计中可能很有用。 公共卫生相关性：炎症与许多疾病，含有心血管疾病的发病机理至关重要。 2（MAC-1）是这些细胞在炎症反应中的多种反应上的最通用的接种，这取决于Mac-1的功能。 1且受体广泛识别的生物学意义可能导致炎症起作用的治疗表S。