Regulatory roles of peptidylarginine deimination in elastogenisis

肽基精氨酸脱亚胺化在弹性生成中的调节作用

• 批准号: 10605290
• 负责人: I-CHENG HO
• 金额: $ 53.59万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605290
• 关键词: Adult; Affect; Age; Aneurysm; Arteries; Biochemical; Biological Process; Cell physiology; Cells; Charge; Chronic Obstructive Pulmonary Disease; Cigarette smoke-induced emphysema; Clinical; Data; Development; Elastic Fiber; Elasticity; Elastin; FBLN5 gene; Fibroblasts; Functional Regeneration; Genetic; Genetically Engineered Mouse; Goals; Health; Human; Impairment; In Vitro; Knowledge; Life; Link; Lung; Lung Compliance; Lung diseases; Mediating; Modeling; Modification; Molecular; Monoclonal Antibodies; Morphology; Mus; Organ; Pathologic; Physiological; Physiology; Post-Translational Protein Processing; Predisposition; Protein-arginine deiminase; Proteins; Proteomics; Pulmonary Emphysema; Reagent; Rheumatoid Arthritis; Role; Site; Skin; Stimulus; Substrate Specificity; Time; Tissues; Untranslated RNA; age related; biophysical techniques; cell type; cigarette smoking; effective therapy; extracellular; human disease; idiopathic pulmonary fibrosis; improved; monomer; novel; novel strategies; novel therapeutic intervention; overexpression; perinatal period; pharmacologic; protein expression; protein function; pulmonary function

Project Summary Elastic fibers provide the elasticity that is essential for the function of many organs/tissues, such as lung, large arteries, and skin. Congenital deficiency or destruction/degradation of elastic fibers can lead to emphysema, arterial aneurysm, and laxity of tissues. Reversely, excessive formation of elastic fibers is a feature of pleuroparenchymal fibroelastosis, which is currently without any effective treatment. Many proteins are modified after they are produced in cells. Such modification can critically influence the function of proteins. One such modification is citrullination, which has been shown to regulate the function of various types of cells. Aberrant citrullination has been observed in many human diseases, such as chronic obstructive lung disease, idiopathic pulmonary fibrosis, and rheumatoid arthritis. Thus, manipulating protein citrullination can be beneficial in many clinical settings. This project is based on a novel observation that citrullination critically regulates the formation of elastic fibers. Its goal is to investigate the role and mechanism of action of citrullination in regulating the formation of elastic fibers and lung function. Molecular, cellular, and biophysical approaches will be deployed to elucidate how citrullination regulates the elastogenesis of fibroblasts (Aim 1) and how citrullination of critical elastogenic proteins is regulated (Aim 2). Reagents detecting the citrullination of the critical elastogenic proteins will be developed to facilitate this endeavor. Finally, genetically engineered mice will be generated to examine cell type-specific and temporal roles of citrullination in modulating the function of lungs and the development of emphysema induced by cigarette smoking (Aim 3). Knowledge gained from this project very likely will uncover novel therapeutic approaches toward many human diseases, such as emphysema and arterial aneurysm.

项目摘要 弹性纤维提供的弹性对于许多器官/组织的功能，例如肺，大型 动脉和皮肤。弹性纤维的先天性缺乏或破坏/降解会导致肺气肿， 动脉动脉瘤和组织的松弛性。相反，弹性纤维的过度形成是 胸膜纤维纤维舒张，目前尚无任何有效治疗。许多蛋白质是 在细胞中产生后修饰。这种修饰可以严重影响蛋白质的功能。一 这种修饰是柠檬化，已证明可以调节各种细胞的功能。 在许多人类疾病（例如慢性阻塞性肺疾病， 特发性肺纤维化和类风湿关节炎。因此，操纵蛋白柠檬酸可以是 在许多临床环境中有益。该项目是基于一个小新颖的观察结果 调节弹性纤维的形成。它的目标是调查行动的作用和机制 柠檬酸在调节弹性纤维和肺功能的形成方面。分子，细胞和生物物理 将部署方法来阐明柠檬酸如何调节成纤维细胞的弹性发生（AIM 1） 以及如何调节临界弹力蛋白的柠檬化（AIM 2）。检测柠檬化的试剂 将开发关键的弹性蛋白来促进这项工作。最后，经过基因工程 将生成小鼠以检查柠檬化在调节中的细胞类型特异性和时间作用 肺的功能和吸烟引起的肺气肿的发展（AIM 3）。知识 从这个项目中获得的很可能会发现许多人类疾病的新型治疗方法， 例如肺气肿和动脉动脉瘤。