Contribution of Macropinocytosis in fibroblast activation and systemic sclerosis

巨胞饮作用在成纤维细胞活化和系统性硬化症中的作用

基本信息

批准号：
10551908
负责人：
Konstantin Tsoyi
金额：
$ 17.6万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10551908
关键词：
Acceleration Actins Address Amiloride Amino Acids Animal Model Apoptosis Attenuated Autoimmune Diseases Automobile Driving Cause of Death Cell Aging Cell Survival Cells Cessation of life Clathrin Complex Complication Data Dedications Dermal Development Disease Effector Cell Endocytosis Environment Extracellular Fluid Extracellular Matrix Fatty Acids Fibroblasts Fibrosis Gene Expression Genetic Transcription Goals High Prevalence Imipramine In Vitro Interstitial Lung Diseases Invaded Laboratories Lung Lung fibrogenesis Mediating Molecular Morbidity - disease rate Mus Myofibroblast Nutrient Organ Organelles Pathogenesis Pathogenicity Patients Pharmaceutical Preparations Phenotype Phosphatidylinositols Phosphotransferases Pinocytosis Play Prevalence Process Production Profibrotic signal Proteins Publishing Pulmonary Fibrosis Research Resistance Respiratory Failure Rheumatism Role Scleroderma Signal Pathway Skin Smooth Muscle Systemic Scleroderma TGFB1 gene Techniques Testing Therapeutic Therapeutic Intervention Tuberous Sclerosis United States United States Food and Drug Administration Vacuolar Protein Sorting Vascular Diseases Virus cancer cell cell motility clinical heterogeneity effective therapy extracellular feasibility testing fibrogenesis in vivo indium-bleomycin inhibitor loss of function member migration mortality pharmacologic polypeptide programs response skin fibrosis therapeutic target transcriptome sequencing uptake

项目摘要

PROJECT SUMMARY/ABSTRACT This R21 proposal describes a two-year research plan that will facilitate research program dedicated to determining the role of macropinocytosis in systemic sclerosis (SSc, scleroderma) and SSc-associated interstitial lung disease (ILD). SSc is an autoimmune disorder, which is manifested by skin fibrosis, vasculopathy and the fibrosis of internal organs. The prevalence of SSc is estimated to range from 50 to 300 per million across the world, with one of the highest prevalence rates observed in the United States at 240 per million. Because of its clinical heterogeneity, SSc is a challenging disease to manage which results in the highest disease mortality among the rheumatologic diseases. ILD is the most common lung complication of SSc and is associated with increased mortality. ILD occurs in up to 80% of patients with SSc, with 25–30% developing a severe progressive form of SSc-ILD leading to eventual respiratory failure and death. Little is known about the molecular mechanisms involved in the pathogenesis of SSc and SSc-ILD. This project will focus on elucidating the key roles of macropinocytosis in skin and lung fibrogenesis, as well as its therapeutic targeting. Macropinocytosis is an actin-dependent but clathrin-independent endocytic process that mediates the nonselective internalization of extracellular contents, such as proteins, cell debris, or viruses. Macropinocytosis has been shown to be involved in cell survival, migration and invasion by providing nutrients (e.g., free amino acids and polypeptides) from extracellular environment. However, its role in scleroderma and organ fibrogenesis is unknown. Our preliminary findings suggest that inhibition of macropinocytosis attenuates dermal myofibroblast differentiation and pulmonary fibrosis in mice. Furthermore, we found that vacuolar protein sorting 34 (Vps34), a sole member of class III phosphoinositide-3-kinase (PI3K), is involved in macropinocytosis and fibroblast activation. Based on published and our preliminary findings, we hypothesize that increased macropinocytosis promotes the development of dermal and lung fibrosis in SSc. Thus, its inhibition exerts anti-fibrotic effects in the animal model of skin fibrosis by reducing profibrotic responses in activated fibroblasts. We also hypothesize that Vps34 is essential for macropinocytosis, which in turn confers to fibroblast activation. We will test our hypotheses by addressing the following Specific Aims: Specific Aim #1: To demonstrate that macropinocytosis inhibition attenuates dermal and lung fibrosis in mice by inhibiting fibroblast to myofibroblast differentiation, ECM production, and migration. Specific Aim #2: To demonstrate that Vps34 is a key protein in macropinosome formation and contributes to profibrotic responses of dermal and lung fibroblasts.

项目摘要/摘要该R21提案描述了一项为期两年的研究计划，该计划将促进专门针对的研究计划确定大型细胞增多症在全身性硬化症（SSC，硬皮病）和SSC相关的间构作用肺部病（ILD）。 SSC是一种自身免疫性疾病，由皮肤纤维化，血管病和内部器官的纤维化。 SSC的患病率估计在整个百万到300到300范围内世界，是美国观察到的最高患病率之一，每百万分之240。因为它临床异质性，SSC是一种挑战性疾病，可导致疾病死亡率最高在风湿病中。 ILD是SSC最常见的肺并发症，与死亡率增加。 ILD发生在多达80％的SSC患者中，有25–30％的患者发生严重的进行性 SSC-ild的形式导致最终呼吸衰竭和死亡。关于分子知之甚少 SSC和SSC-ILD的发病机理涉及的机制。该项目将重点阐明钥匙大型细胞增多症在皮肤和肺纤维发生及其治疗靶向的作用。大型细胞增多症是肌动蛋白依赖性但独立于网格蛋白独立的内吞过程，介导了非选择性的内在化细胞外含量，例如蛋白质，细胞碎屑或病毒。大型细胞增多症已被证明涉及在细胞存活中，通过提供营养（例如游离氨基酸和多肽）来迁移和侵袭细胞外环境。但是，其在硬皮病和器官纤维发生中的作用尚不清楚。我们的初步调查结果表明，抑制大细胞增多症会减弱皮肤成肌纤维细胞的分化和小鼠肺纤维化。此外，我们发现真空蛋白排序34（VPS34），一个唯一的成员 III类磷酸肌醇-3-激酶（PI3K）参与大型细胞增多症和成纤维细胞激活。基于发表和我们的初步发现，我们假设增加的大型细胞增多症促进了 SSC中真皮和肺纤维化的发展。这，其抑制作用在通过减少活化成纤维细胞中的纤维化反应，皮肤纤维化的动物模型。我们也是假设VPS34对于大型细胞增多症至关重要，进而赋予成纤维细胞激活。我们将通过解决以下特定目的来检验我们的假设：特定目的＃1：证明这一点大型细胞增多症抑制通过抑制成纤维细胞对肌纤维细胞抑制小鼠的皮肤和肺纤维化分化，ECM生产和迁移。特定目的＃2：证明VPS34是关键蛋白大型体体的形成，并有助于真皮和肺成纤维细胞的纤维化反应。