The Role of Carboxypeptidase B and its Substrates in Rheumatoid Arthritis

羧肽酶 B 及其底物在类风湿性关节炎中的作用

基本信息

批准号：
7895844
负责人：
Jason Song
金额：
$ 12.54万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7895844
关键词：
Acute Address Alleles Animal Model Anti-Inflammatory Agents Anti-inflammatory Antibodies Arginine Arthritis Autoantibodies Autoimmune Process Bioinformatics Biological Assay Bioluminescence Biotechnology Blood Clot Blood Platelets Blood coagulation Bradykinin Bradykinin B2 Receptor C-terminal Carboxypeptidase B Carboxypeptidase U Cartilage Cells Characteristics Chemotactic Factors Chemotaxis Cleaved cell Clinical Coagulation Process Collagen Complement Complement 3a Complement 5a Data Databases Deposition Development Plans Disease Disease Progression Disease susceptibility Dose Enzyme-Linked Immunosorbent Assay Enzymes Etiology Exhibits Fibrin Fibrinolysis Flow Cytometry Funding Genes Genetic Genetic Polymorphism Genotype Half-Life Hepatocyte Histologic Human Hyperplasia Immunoblotting Immunohistochemistry Immunology In Vitro Individual Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Infiltrate Inflammatory Response Instruction Joints K-Series Research Career Programs Knockout Mice Laboratories Lead Leukocyte Chemotaxis Link Linkage Disequilibrium Liver Lysine Mediating Megakaryocytes Mentors Migration Assay Minor Modeling Molecular Molecular Biology Molecular Weight Morbidity - disease rate Mus Nuclear Pathogenesis Pathway interactions Patients Peritonitis Physicians Plasma Plasmin Play Population Predisposition Principal Investigator Property Proteins Public Health Registries Reporting Research Research Activity Research Personnel Reverse Transcriptase Polymerase Chain Reaction Rheumatoid Arthritis Role Sampling Scientist Series Severities Staining method Stains Students Supervision Synovial Fluid System T-Cell Activation Thrombin Tissues Training Variant Wild Type Mouse Zymosan arthropathies base bone career development case control distraction experience genetic association in vitro Model in vivo inflammatory marker inhibitor/antagonist insight interest meetings migration mortality neutrophil novel therapeutic intervention osteopontin platelet typing prevent protein expression research study rheumatologist

项目摘要

DESCRIPTION (provided by applicant): Dr. Song is a rheumatologist with training in immunology and molecular biology. There is significant evidence suggesting underlying dysregulation not only of inflammatory responses but also of the coagulation system in rheumatoid arthritis (RA). Dr. Song's research interests lie in investigating how joint inflammation in RA interplays with dysregulation of the coagulation system. To date, little is known about the molecular links between inflammation and coagulation in RA and other inflammatory diseases. Dr. Song has generated preliminary data that demonstrates a marked increase in arthritis in an animal model with deficiency of carboxypeptidase B (CPB), a plasma enzyme that contributes to the stability of blood clots. This data led him to propose the hypothesis that CPB is involved in the interaction of inflammation and coagulation in RA. Interestingly, it has been found that CPB interacts with several proinflammatory substrates and removes carboxy-terminal arginines. In this KOS, he proposes to determine how CPB down-regulates inflammation in arthritis by acting on proinflammatory substrates including osteopontin, complements components and bradykinin. This application also details a carefully thought out career development plan that includes rich interaction with other laboratories at Stanford, attendance at seminars and scientific meetings, supervision of students and technicians, and classes in immunology and bioinformatics. Dr. Song has strong institutional support that will allow him to focus on these studies with minimal distraction to non-research activities. This KGB mentored Clinical Scientist Career Development Award will facilitate Dr. Song's transition from a rheumatologist to a physician scientist who is fully competent to investigate the link between inflammation and coagulation in his own academic laboratory through independent, investigator-initiated funding. RELEVANCE (See instructions): This research is directly related to public health as 1% of the US population suffers from RA, and RA is a significant cause bf morbidity and mortality. Out data demonstrate that CPB is a natural modulator of inflammation, in addition to its recognized role as a fibrinolysis inhibitor. The proposed experiments will provide insights into the pathogenesis of RA which could lead to new therapeutic approaches.

描述（由申请人提供）：Song博士是风湿病学家，接受了免疫学和分子生物学培训。有大量证据表明，不仅炎症反应的基本失调，而且还表明类风湿关节炎（RA）中的凝血系统。 Song博士的研究兴趣在于调查与凝血系统失调的RA相互作用中的关节炎症。迄今为止，关于RA和其他炎症性疾病的炎症与凝结之间的分子联系知之甚少。 Song博士产生了初步数据，该数据表明，在动物模型中，关节炎显着增加，羧肽酶B（CPB）是一种血浆酶，这是一种有助于血液凝块的稳定性。该数据使他提出了以下假设：CPB参与RA中炎症和凝结的相互作用。有趣的是，已经发现CPB与几种促炎性底物相互作用并去除羧基末端精氨酸。在此KO中，他提议通过对促炎性底物作用（包括骨桥蛋白，补充成分和Bradykinin）来确定CPB如何通过作用于促炎性底物来下调关节炎的炎症。该应用程序还详细介绍了一项经过深思熟虑的职业发展计划，其中包括与斯坦福大学其他实验室的丰富互动，参加研讨会和科学会议，对学生和技术人员的监督以及免疫学和生物信息学的课程。 Song博士拥有强大的机构支持，这将使他能够专注于这些研究，以最少的分心非研究活动。克格勃指导的临床科学家职业发展奖将促进宋博士从风湿病学家向医师科学家的过渡，他们完全有能力通过独立，研究人员发起的资金来调查其自己的学术实验室中的炎症与凝结之间的联系。相关性（请参阅说明）：这项研究与公共卫生直接相关，因为1％的美国人口患有RA，RA是BF的发病率和死亡率的重要原因。数据表明，除了公认的纤维蛋白溶解抑制剂的作用外，CPB是炎症的天然调节剂。提出的实验将提供有关RA发病机理的见解，这可能导致新的治疗方法。