Interactions and convergence of innate inflammation and extrinsic coagulation pathways

先天性炎症和外源性凝血途径的相互作用和融合

基本信息

批准号：
10113518
负责人：
David A Rubenstein
金额：
$ 19.28万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-24 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10113518
关键词：
Address Adhesions Area Atherosclerosis Biological Assay Biological Process Blood Coagulation Factor VII Blood Platelets Blood Vessels Cardiovascular Diseases Cause of Death Cell physiology Cell surface Cessation of life Coagulation Process Complement Complement 1q Complement Activation Deposition Development Disease Disease Progression Event Exposure to Factor X Fibrin Fibroblasts Foundations Goals Health Immune System Diseases Immunologics Inflammation Inflammatory Innate Immune System Intervention Kinetics Lead Link Mediating Mediator of activation protein Minor Natural Immunity Pathologic Pathology Pathway interactions Pericytes Pharmacology Physiological Platelet Activation Play Population Process Prothrombin Public Health Recording of previous events Regulation Research Risk Factors Role Severity of illness Signal Transduction Site Smooth Muscle Myocytes Surface System Testing Therapeutic Therapeutic Effect Thrombin Thromboplastin Thrombosis Time United States Vascular Diseases Vascular Smooth Muscle Western World Work base complement 1q receptor design immune activation in vitro Model innovation insight new therapeutic target novel receptor response success targeted treatment therapeutic target therapeutically effective thrombotic

项目摘要

Project Summary It is well established that vascular diseases involve and can be characterized by altered inflammatory and thrombotic processes. In the past, these processes were thought to be distinct and unrelated but emerging evidence suggests that there are important connections between inflammatory and thrombotic activities. gC1qR has surfaced as a salient receptor for many innate inflammatory disease processes and there have been links identified between gC1qR activity and intrinsic coagulation. However, it has never been investigated whether or not gC1qR activity, as mediated by C1q, leads to altered extrinsic coagulation, the physiologically and pathologically relevant coagulation system. We have shown for the first time that C1q activation of gC1qR expressed on vascular smooth muscle cell and adventitial fibroblasts enhances the expression of tissue factor. Tissue factor expression is the salient rate limiting step for extrinsic coagulation activation. Our long-term goal is to elucidate the relevance and significance of this converged inflammatory/thrombotic signaling on vascular disease progression. In parallel to this, we aim to identify the underlying mechanism(s) responsible for the observed alterations on vascular health and vascular disease progression. The specific objective for this proposal is to investigate the significance of gC1qR activity on tissue factor expression and subsequent activation/progression of extrinsic coagulation to the level of prothrombin activation. We will observe these interactions using our in vitro models of vascular health, utilizing relevant smooth muscle cells, fibroblasts and platelets to characterize disease progression. Our global hypothesis is that activation of the innate immune system leads to altered gC1qR activity/signaling, which subsequently induces altered tissue factor expression and extrinsic coagulation activation. This work would show, for the first time, a distinct and specific link and convergence of innate inflammatory pathways with the extrinsic coagulation pathways; while characterizing the underlying mechanisms responsible for these responses. We further hypothesize that these changes are mediated by altered Akt signaling within vascular smooth muscle cells and adventitial fibroblasts. Guided by our preliminary work, we will test our hypothesis by pursing 2 specific aims: 1) evaluate complement regulation of vascular smooth muscle cell and adventitial fibroblast tissue factor expression and to elucidate the underlying mechanisms responsible for observed changes and 2) evaluate thrombotic changes in response to altered vascular smooth muscle cell and adventitial fibroblast tissue factor expression. The proposed work is innovative because we will determine whether or not gC1qR acts as a transitional link between innate inflammation and extrinsic coagulation and furthermore, we will illustrate that changes to innate immunity can lead to altered extrinsic coagulation activity. We believe that the success of this proposal will have a significant positive impact on the understanding of vascular disease development, provide new insight into vascular disease progression and may help us to identify new candidate targets for disease intervention.

项目摘要众所周知，血管疾病涉及并且可以通过改变的炎症和特征血小板过程。过去，这些过程被认为是独特的，无关但出现了有证据表明，炎症和血栓性活动之间存在重要的联系。 GC1QR已成为许多先天炎症过程的显着受体，并且有在GC1QR活性与内在凝结之间确定了联系。但是，它从未被调查过 C1Q介导的GC1QR活性是否导致外部凝血改变，在生理上和病理相关的凝血系统。我们首次表明了GC1QR的C1Q激活在血管平滑肌细胞上表达，外在成纤维细胞增强了组织因子的表达。组织因子表达是外在凝结激活的显着速率限制步骤。我们的长期目标是为了阐明这种融合的炎症/血栓信号在血管上的相关性和意义疾病进展。同时，我们旨在确定负责该机制的基本机制观察到血管健康和血管疾病进展的改变。为此的具体目标建议是研究GC1QR活性对组织因子表达的重要性，然后外在凝结到凝血酶原激活水平的激活/进展。我们将观察到这些利用相关平滑肌细胞，成纤维细胞和血小板以表征疾病进展。我们的全球假设是激活先天免疫系统导致GC1QR活性/信号传导发生变化，随后诱导组织因子表达改变和外部凝血激活。这项工作将首次显示一个独特而特定的链接，并且先天炎症途径与外在凝结途径的收敛；同时表征负责这些反应的基本机制。我们进一步假设这些变化是由血管平滑肌细胞中的AKT信号改变和外在成纤维细胞介导的。指导我们的初步工作，我们将通过追求2个特定目的来检验我们的假设：1）评估补充法规血管平滑肌细胞和外在成纤维细胞组织因子表达的表达，并阐明负责观察到的变化的基本机制和2）评估响应于改变的血管平滑肌细胞和外在成纤维细胞组织因子表达。拟议的工作是创新性，因为我们将确定GC1QR是否充当先天性之间的过渡联系炎症和外部凝血以及此外，我们将说明先天免疫的变化可以导致外部凝血活性改变。我们认为，该提议的成功将有一个对对血管疾病发展的理解的重大积极影响，为血管疾病的进展，可能有助于我们确定新的疾病干预候选靶标。