Cadherin-11 growth factor receptor interactions in RA fibroblast hyperplasia

Cadherin-11生长因子受体在RA成纤维细胞增生中的相互作用

• 批准号: 8655515
• 负责人: Erika Heidi Noss
• 金额: $ 13.14万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8655515
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Apoptosis; Arthritis; Autoimmune Diseases; Autoimmune Process; Basic Science; Biochemical; Biological Assay; Biology; Blood Platelets; Cadherins; Cartilage; Cell Adhesion Molecules; Cell Differentiation process; Cell Proliferation; Cell Survival; Cells; Chemicals; Clinical; Co-Immunoprecipitations; Collaborations; Complement; Development; Disease; Environment; Fibroblasts; Flow Cytometry; Funding; Goals; Grant; Growth; Growth Factor Receptors; Human; Hyperplasia; Immune; Immunofluorescence Immunologic; In Situ; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Joints; Laboratories; Ligands; Link; Mentors; Mitogen-Activated Protein Kinase Kinases; Modeling; Mus; Nature; PDGF receptor tyrosine kinase; Pathogenesis; Pathology; Pathway interactions; Patients; Physicians; Platelet-Derived Growth Factor Receptor; Population; Process; Production; Receptor Activation; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Research; Research Personnel; Research Proposals; Research Training; Rheumatoid Arthritis; Rheumatology; Role; Scientist; Signal Pathway; Signal Transduction; Small Interfering RNA; Stromal Cells; Synovial Membrane; Synovitis; Testing; Tissue Model; Tissues; Training; Translational Research; bone; cadherin-11; career; effective therapy; human PDGFRL protein; in vivo; inhibitor/antagonist; joint destruction; joint function; new therapeutic target; novel; prevent; public health relevance; receptor; receptor expression; skills; therapeutic target; tumor

DESCRIPTION (provided by applicant): This K08 Mentored Clinical Scientist application provides a comprehensive plan to develop the scientific expertise, professional skills, and collaborations the applicant will need to transition to an independent academic research career. The research proposal examines a newly identified interaction between the cell adhesion molecule cadherin-11 (cad11) and receptor tyrosine kinase (RTK) platelet-derived growth factor receptors (PDGFRs) on rheumatoid arthritis (RA) synovial fibroblasts. During RA, marked activation and hyperplasia of synovial fibroblasts contributes to all aspects of RA disease pathogenesis, although the mechanisms responsible for fibroblast hyperplasia are poorly understood. The sponsor's laboratory previously identified cad11 as a specific marker and regulator of synovial fibroblast function in inflammatory arthritis. Since interactions between cadherins and RTKs like PDGFRs influence cell proliferation and differentiation in tumor and other tissue models, the applicant hypothesized that interactions between cad11 and PDGFRs may be important to regulate synovial fibroblast proliferation and survival in RA. This proposal develops three distinct aims to better understand the biology of this interaction and its role in inflammatory arthritis. Aim 1 employs in vitro studies using human RA synovial fibroblasts to define the signaling pathways downstream of cad11 and PDGFR that promote synovial fibroblast proliferation and survival. Aim 2 uses both biochemical and immunofluorescence approaches to understand the nature of the physical association between these two molecules and to determine its effect on PDGFR stability and signaling intensity. Aim 3 demonstrates the relevance of cad11 PDGFR interactions to synovitis development by using a mouse inflammatory arthritis model to examine the effect of loss of cad11 expression on fibroblast proliferation, survival, and PDGFR expression in vivo. This proposal is core to the longer- range research goals of the applicant to better understand the mechanisms important for fibroblast accumulation and activation in RA, with the hope that identifying fibroblast-specific therapeutic targets that may provide more effective treatments for RA patients. To complement the research proposal, the applicant presents a training plan that details specific coursework to increase her scientific expertise and promote her professional development. She has chosen a mentor with a long-track record of developing physician scientists and has established a network of independent investigators to provide both scientific and career advice. In combination, the training and research plans outlined in this proposal provide a comprehensive platform to support the applicant's development into an independently-funded, academic researcher in rheumatology-focused basic and translational research.

描述（由申请人提供）：此K08指导的临床科学家应用程序提供了一项全面的计划，以开发申请人需要过渡到独立的学术研究职业的科学专业知识，专业技能和合作。该研究提案研究了细胞粘附分子Cadherin-11（CAD11）和受体酪氨酸激酶（RTK）血小板衍生的生长因子受体（PDGFRS）在类风湿关节炎（RA）促性促性炎性疾病（RA）造基体性成纤维成纤维细胞上的相互作用。在RA期间，滑膜成纤维细胞的明显激活和增生有助于RA疾病发病机理的各个方面，尽管对成纤维细胞增生的机制知之甚少。发起人的实验室先前将CAD11确定为炎性关节炎中滑膜成纤维细胞功能的特定标记和调节剂。由于钙粘着蛋白与PDGFR（PDGFRS）之间的相互作用会影响肿瘤和其他组织模型的细胞增殖和分化，因此申请人假设CAD11和PDGFR之间的相互作用对于调节RA中的滑膜成纤维成纤维细胞增殖和生存率可能很重要。该提案旨在更好地了解这种相互作用的生物学及其在炎症性关节炎中的作用。 AIM 1使用人RA滑膜成纤维细胞采用体外研究来定义CAD11和PDGFR下游的信号通路，从而促进滑膜成纤维细胞增殖和存活。 AIM 2同时使用生化和免疫荧光方法来了解这两个分子之间物理关联的性质，并确定其对PDGFR稳定性和信号强度的影响。 AIM 3通过使用小鼠炎症性关节炎模型来检查CAD11表达对成纤维细胞增殖，存活和PDGFR在Vivo中的影响的影响，证明了CAD11 PDGFR相互作用与滑膜炎发育的相关性。该建议是申请人长期研究目标的核心，以更好地了解RA中成纤维细胞积累和激活重要的机制，希望鉴定成纤维细胞特异性的治疗靶标，这些靶标可能会为RA患者提供更有效的治疗方法。为了补充研究建议，申请人提出了一项培训计划，详细介绍了特定的课程，以提高她的科学专业知识并促进她的专业发展。她选择了一位具有发展医师科学家的长期记录的导师，并建立了一个独立研究人员网络，以提供科学和职业建议。结合起来，本提案中概述的培训和研究计划为支持申请人的发展提供了一个全面的平台，以风湿病学基础和转化研究的独立资助，学术研究员。