THE UBIQUITIN PATHWAY IN CORNEAL SCARRING

角膜疤痕中的泛素通路

• 批准号: 10581233
• 负责人: AUDREY M BERNSTEIN
• 金额: $ 36.68万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581233
• 关键词: 3-Dimensional; Acrylamides; Actins; Acute; Affect; Animals; Anti-Inflammatory Agents; Apoptosis; Appearance; Binding; Biological Assay; Biological Models; Blindness; Bone Marrow; Bundling; Cell Adhesion; Cell Communication; Cell Nucleus; Cell surface; Cells; Chronic; Cicatrix; Coculture Techniques; Collagen; Communication; Complex; Cornea; Corneal Injury; Cytoskeleton; Cytosol; Data; Deposition; Development; Encapsulated; Endocytosis; Environment; Equilibrium; Excision; Exhibits; Extracellular Matrix; Family suidae; Fibroblasts; Fibrosis; Flow Cytometry; Foundations; G3BP1 gene; Gel; Genetic Transcription; Goals; Hour; Human; Hydrogels; Immune; Immunohistochemistry; In Situ Nick-End Labeling; Infection; Infection prevention; Injury; Integrin alphaV; Integrins; Knockout Mice; Legal patent; Ligation; Macrophage; Mediating; Mediator; Modeling; Molecular; Monocular Blindness; Mus; Myofibroblast; Nuclear; Organ Culture Techniques; Oryctolagus cuniculus; Outcome; PTPRC gene; Pathologic; Pathway interactions; Phase; Phenotype; Play; Proteins; Recycling; Research; Role; Signal Transduction; Small Interfering RNA; System; TP53 gene; Testing; Therapeutic; Time; Tissues; Transforming Growth Factor beta; Trauma; Ubiquitin; Vision; corneal regeneration; corneal scar; immune cell infiltrate; in vivo; knock-down; mouse model; novel; prevent; response; therapeutic siRNA; tissue repair; ubiquitin isopeptidase; wound; wound healing

Project Summary: The ubiquitin pathway in corneal scarring Scarring in the cornea resulting from injury, trauma, or infection can lead to debilitating opacities and permanent vision loss. Acute scarring, similar to chronic fibrosis, is characterized by immune cell infiltration and the persistence of cells termed myofibroblasts. We have found that the deubiquitinase (DUB) USP10 is a key regulator of scarring pathways in the cornea. Knockdown of USP10 in vivo leads to a significant reduction in the development of myofibroblasts, cell apoptosis, the presence of CD45+ immune cells, and fibrotic extracellular matrix in a healing wound. We are proposing to test the central hypothesis that USP10 is a key regulator of myofibroblast persistence in a corneal scar via its multi- factorial role in wound healing. Specifically, since USP10 is a DUB for αv-integrins and p53, in Specific Aim 1 we will unravel the complex role of USP10 in integrin recycling and p53 dynamics in primary human corneal fibroblasts and in mice in vivo. The communication between fibroblasts and macrophages plays a critical role in scarring outcomes. In Specific Aim 2 we will develop novel 3D and 2.5D hydrogel systems with “tunable stiffness” that mimic a 3D environment close to the stiffness of the healing cornea. Using these hydrogels, mouse corneal fibroblasts will be cocultured with mouse bone marrow derived macrophages (M0/M1/M2) to elucidate the role of USP10 in macrophage-mediated myofibroblast development and contraction. In Specific Aim 3 using three separate mouse models we will assess the role of USP10 in immune cell infiltration into a corneal wound.

项目摘要：角膜疤痕中的泛素途径 因受伤，创伤或感染而导致的角膜疤痕会导致衰弱和 永久视力丧失。与慢性纤维化相似的急性疤痕以免疫细胞为特征 浸润和细胞的持久性称为肌纤维细胞。我们发现去泛素酶 （DUB）USP10是角膜中疤痕途径的关键调节器。 USP10 In Vivo铅的敲低 为了显着降低肌纤维细胞的发展，细胞凋亡，CD45+的存在 免疫细胞和愈合伤口中的纤维化细胞外基质。我们建议测试中央 假设USP10是角膜疤痕中肌纤维细胞持久性的关键调节剂。 阶乘在伤口愈合中的作用。具体而言，由于USP10是αV-整合蛋白和p53的配音，因此 目标1我们将揭示USP10在整合素回收和p53动态中的复杂作用 人角膜成纤维细胞和体内小鼠。成纤维细胞和 巨噬细胞在疤痕结局中起着至关重要的作用。在特定目标2中，我们将开发新颖的3D和 2.5D水凝胶系统具有“可调刚度”，模仿3D环境接近刚度 治愈角膜。使用这些水凝胶，小鼠角膜成纤维细胞将与小鼠骨头共培养 骨髓衍生的巨噬细胞（M0/M1/M2）阐明了USP10在巨噬细胞介导的 肌纤维细胞发育和收缩。在特定的目标3中，使用三种单独的鼠标模型我们 将评估USP10在免疫细胞浸润到角膜伤中的作用。

项目成果

Is Autophagy Dysfunction a Key to Exfoliation Glaucoma?

• DOI: 10.1097/ijg.0000000000000606
• 发表时间: 2018-03
• 期刊: Journal of glaucoma
• 影响因子: 2
• 作者: Wolosin JM;Ritch R;Bernstein AM
• 通讯作者: Bernstein AM

Biocompatibility Assessment of PLCL-Sericin Copolymer Membranes Using Wharton's Jelly Mesenchymal Stem Cells.

• DOI: 10.1155/2016/5309484
• 发表时间: 2016
• 期刊: Stem cells international
• 影响因子: 4.3
• 作者: Inthanon K;Daranarong D;Techaikool P;Punyodom W;Khaniyao V;Bernstein AM;Wongkham W
• 通讯作者: Wongkham W