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: 10442830
• 负责人: I-CHENG HO
• 金额: $ 57.54万
• 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/10442830
• 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; Elastic Fiber; Elasticity; Elastin; FBLN5 gene; Fibroblasts; Functional Regeneration; Genetic; Genetically Engineered Mouse; Goals; Health; Human; Impairment; In Vitro; Knockout Mice; Knowledge; Lead; Life; Link; Lung; Lung Compliance; Lung diseases; Mediating; Modeling; Modification; Molecular; Monoclonal Antibodies; Morphology; Mus; Natural regeneration; Organ; Pathologic; Pharmacology; 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; Translations; Untranslated RNA; age related; base; biophysical techniques; cell type; cigarette smoking; effective therapy; extracellular; human disease; idiopathic pulmonary fibrosis; improved; lung development; monomer; novel; novel strategies; novel therapeutic intervention; overexpression; perinatal period; 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 弹性纤维提供了许多器官/组织功能所必需的弹性，如肺、大的 动脉和皮肤。弹性纤维的先天缺陷或破坏/降解可导致肺气肿， 主动脉瘤和组织松弛。相反，弹性纤维的过度形成是 胸膜实质成纤维细胞增生症，目前没有任何有效的治疗方法。许多蛋白质是 它们在细胞中产生后进行修饰。这种修饰会严重影响蛋白质的功能。一 这种修饰就是瓜氨酸化，它已经被证明可以调节各种类型的细胞的功能。 在许多人类疾病中都观察到了异常的瓜氨酸化，例如慢性阻塞性肺病， 特发性肺纤维化和类风湿性关节炎。因此，操控蛋白质的瓜氨酸化可以 在许多临床环境中有益。这个项目是基于一项新的观察结果，即瓜氨酸的临界作用 调节弹性纤维的形成。它的目标是研究作用和机制的作用。 瓜氨酸在调节弹性纤维形成和肺功能中的作用。分子、细胞和生物物理 将采用多种方法来阐明瓜氨酸化如何调节成纤维细胞的弹力形成(目标1)。 以及关键弹性蛋白的瓜氨酸化是如何调节的(目标2)。检测瓜氨酸化的试剂 许多关键的弹性蛋白将被开发出来，以促进这一努力。最后，基因工程 将产生小鼠来检查细胞类型特定的和瓜氨酸化在调节细胞周期中的作用。 吸烟引起的肺功能和肺气肿的发展(目标3)。知识 从这个项目中获得的成果很可能会发现许多人类疾病的新治疗方法， 例如肺气肿和动脉瘤。