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 弹性纤维提供对于许多器官/组织（例如肺、大血管、血管和/或血管）的功能至关重要的弹性。 动脉和皮肤。弹性纤维的先天性缺陷或破坏/降解可导致肺气肿， 动脉瘤和组织松弛。然而，弹性纤维的过度形成是一个特征， 胸膜实质纤维弹性组织增生症，目前没有任何有效的治疗方法。许多蛋白质 在细胞中产生后进行修饰。这种修饰可以严重影响蛋白质的功能。一 这种修饰是瓜氨酸，瓜氨酸已显示出调节各种类型细胞的功能。 在许多人类疾病中观察到异常的瓜氨酸，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，操纵瓜氨酸蛋白可以是 在许多临床环境中有益。该项目基于一项新的观察， 调节弹性纤维的形成。其目的是研究的作用和作用机制， 瓜氨酸调节弹性纤维的形成和肺功能。分子、细胞和生物物理 将采用各种方法阐明瓜氨酸如何调节成纤维细胞的弹性发生（目标1） 以及瓜氨酸是如何调节关键的弹性蛋白的（目标2）。瓜氨酸检测试剂 的关键弹性蛋白将被开发，以促进这一奋进。最后，基因工程 将产生小鼠以检查瓜氨酸在调节细胞中的细胞类型特异性和时间作用。 肺功能和吸烟引起的肺气肿的发展（目的3）。知识 从这个项目中获得的信息很可能会发现针对许多人类疾病的新的治疗方法， 例如肺气肿和动脉瘤。