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：角膜瘢痕形成中的泛素途径 由损伤、创伤或感染引起的角膜瘢痕可导致使人衰弱的混浊， 永久性视力丧失急性瘢痕形成与慢性纤维化相似，其特征在于免疫细胞 浸润和称为肌成纤维细胞的细胞的持续存在。我们发现去泛素化酶 (DUB)USP 10是角膜瘢痕形成途径的关键调节剂。USP 10体内电极导线的敲除 肌成纤维细胞的发育、细胞凋亡、CD 45+的存在显着减少 免疫细胞和纤维化细胞外基质。我们建议测试中央 假设USP 10是角膜瘢痕中肌成纤维细胞持久性的关键调节因子， 在伤口愈合中的因素作用。具体而言，由于USP 10是α v-整联蛋白和p53的DUB， 目的1：我们将阐明USP 10在整合素循环和原发性肝癌中p53动力学中的复杂作用。 人角膜成纤维细胞和小鼠体内。成纤维细胞与 巨噬细胞在瘢痕形成结果中起关键作用。在具体目标2中，我们将开发新的3D和 具有“可调刚度”的2.5D水凝胶系统，其模拟接近于水凝胶的刚度的3D环境。 愈合角膜使用这些水凝胶，小鼠角膜成纤维细胞将与小鼠骨共培养 骨髓源性巨噬细胞（M0/M1/M2），以阐明USP 10在巨噬细胞介导的 肌成纤维细胞的发育和收缩。在Specific Aim 3中，使用三种不同的小鼠模型， 将评估USP 10在免疫细胞浸润到角膜伤口中的作用。

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