Provisional Matrix Citrullination as an activator of Fibroblasts in Interstitial Lung Disease

临时基质瓜氨酸化作为间质性肺疾病成纤维细胞的激活剂

基本信息

批准号：
9230781
负责人：
Victoria Stefanelli
金额：
$ 4.4万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9230781
关键词：
Adhesions Affect American Animal Model Animals Apoptosis Apoptotic Arginine Arginine deiminase Behavior Binding Binding Sites Biochemical Biological Assay Biology Biotechnology Bleomycin Blood Vessels Cell Adhesion Cell physiology Cell-Matrix Junction Cells Characteristics Chronic Cicatrix Collaborations Communication Deposition Deterioration Diagnosis Disease Disease Progression Doctor of Philosophy Enzymes Extracellular Matrix Extracellular Matrix Proteins Extracellular Protein Fibrin Fibrinogen Fibrinolysis Pathway Fibroblasts Fibronectins Fibrosis Focal Adhesions Genetic Goals Hamman-Rich syndrome Health Immunologics Immunology procedure Inflammation Inflammatory Integrin Binding Integrins Interstitial Lung Diseases Knowledge Leadership Lung Lung diseases Malignant - descriptor Malignant Neoplasms Mediating Migration Assay Modeling Modification Molecular Multiple Sclerosis Myofibroblast Onset of illness Pathology Patients Phenotype Positioning Attribute Post-Translational Protein Processing Process Proteins Pulmonary Fibrosis Research Resistance Resolution Rheumatoid Arthritis Role Signal Transduction Smoking Survival Rate TdT-Mediated dUTP Nick End Labeling Assay Techniques Therapeutic Intervention Training Treatment Efficacy Western Blotting biophysical techniques career cell behavior chemokine early onset expectation extracellular human disease improved in vivo indium-bleomycin inhibitor/antagonist mechanotransduction migration nanobodies novel novel strategies public health relevance skills targeted delivery targeted treatment

项目摘要

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a lethal condition involving progressive scarring of the lungs that affects 50 in every 100,000 Americans. Its pathologies include aberrant and chronic deposition of provisional extracellular matrix (ECM) proteins-including fibrin and fibronectin- as well as prominent amounts of post-translational modifications to these proteins in the form of citrullination. Importantly, citrullination affects arginine residues, including those accessible in RGD and PHSRN motifs found in fibrin and fibronectin, and thus such modifications are expected to have an influence on local fibroblast behavior mediated to altered integrin interactions. IPF is also associated with an "activated" fibroblast phenotype including characteristics such as invasiveness, resistance to apoptosis, and secretion of excessive ECM proteins. The overall hypothesis is that prolonged interaction of fibroblasts with these citrullinated provisional ECM proteins is responsible for altered fibroblast phenotype. This hypothesis will be explored in three specific aims. In the first, fibroblast cell behaviors including cell attachment, spreading, migration, apoptotic resistance, and secretory profile - including that of chemokines, ECM molecules, and degradation enzymes-will be evaluated in the presence of fibrin, fibrinogen, and fibronectin that has or has not been citrullinated. In the second, the mechanism for these altered fibroblasts will be explored by evaluating changes in specific integrins' binding capacities and activation. Finally, in the third aim, the in vivo efficacy of a targeted treatment that inhibits citrullinated will be evaluated in bleomycin-induced Thy1(-/-) model of IPF. This research is significant because it explores a novel mechanism for fibroblast activation in IPF, which may ultimately suggest a new class of early-stage interventional therapy. It therefore possesses great translational potential. It is als significant because it investigates a fundamental cell-ECM interaction that is prevalent in a wide-variety of chronic inflammatory conditions, including rheumatoid arthritis, malignant cancers, and multiple sclerosis, and it thus has the potential to enhance our understanding of both the onset and progressions many different serious human diseases. This proposal serves at the center of the applicant's training plan allowing her to expand her scientific knowledge, technical proficiencies, communication skills, and leadership capabilities as she prepares for a challenging career in biotechnology.

描述（由申请人提供）：特发性肺纤维化 (IPF) 是一种涉及肺部进行性疤痕的致命疾病，每 100,000 名美国人中就有 50 人受到影响，其病理包括临时细胞外基质 (ECM) 蛋白（包括纤维蛋白和纤维蛋白）的异常和慢性沉积。纤连蛋白以及这些蛋白质以瓜氨酸化形式进行的大量翻译后修饰。瓜氨酸化影响精氨酸残基，包括在纤维蛋白和纤连蛋白中发现的RGD和PHSRN基序中可接近的精氨酸残基，因此这种修饰预计会对介导改变的整联蛋白相互作用的局部成纤维细胞行为产生影响，也与“激活的”成纤维细胞表型相关。包括侵袭性、抗细胞凋亡和分泌过量 ECM 蛋白等特征。总体假设是成纤维细胞与这些细胞的长期相互作用。瓜氨酸临时 ECM 蛋白负责成纤维细胞该假设将在三个具体目标中进行探索，首先，将评估成纤维细胞的行为，包括细胞附着、扩散、迁移、细胞凋亡抵抗和分泌特征（包括趋化因子、ECM 分子和降解酶的行为）。已或未瓜氨酸化的纤维蛋白、纤维蛋白原和纤连蛋白的存在第二，将通过评估特定的变化来探索这些改变的成纤维细胞的机制。最后，在第三个目标中，将在博莱霉素诱导的 Thy1(-/-) IPF 模型中评估抑制瓜氨酸化的靶向治疗的体内疗效。 IPF 中成纤维细胞激活的新机制，最终可能提出一种新的早期介入治疗方法，因此它具有巨大的转化潜力，因为它研究了一种基本的细胞 ECM。这种相互作用在多种慢性炎症性疾病中普遍存在，包括类风湿性关节炎、恶性肿瘤和多发性硬化症，因此有可能增强我们对许多不同严重人类疾病的发病和进展的理解。是申请人培训计划的核心，使她能够在为生物技术领域充满挑战的职业做好准备时扩展她的科学知识、技术熟练程度、沟通技巧和领导能力。