Mechanisms of Trabecular Meshwork Regeneration by Stem Cells

干细胞小梁网再生机制

基本信息

批准号：
9335871
负责人：
Yiqin Du
金额：
$ 38.83万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9335871
关键词：
AMD3100 Address Adverse effects Affinity Aging Anterior Antibodies Aqueous Humor Biological Blindness CXCL12 gene CXCR4 Receptors CXCR4 gene Cell Therapy Cells Cellularity Chemotaxis Clinical Collagen Connective Tissue Data Endothelial Cells Extracellular Matrix Extracellular Matrix Degradation Eye Fibronectins Gene Expression Genes Glaucoma Goals Home environment Homeostasis Homing Human In Vitro Injection of therapeutic agent Lasers Lead Matrix Metalloproteinases Mediating Molecular Molecular Profiling Monitor Multipotent Stem Cells Mus Natural regeneration Operative Surgical Procedures Optic Nerve Pathologic Pathway interactions Patient Noncompliance Patients Perfusion Phagocytes Pharmaceutical Preparations Physiologic Intraocular Pressure Play Regulation Resistance Risk Factors Role Small Interfering RNA Stem cells Structure of sinus venosus of sclera Subfamily lentivirinae System Techniques Testing Tissues Trabecular meshwork structure Transmission Electron Microscopy Transplantation Western Blotting adult stem cell aqueous base biological systems chemokine connective tissue growth factor design ex vivo perfusion experimental study human stem cells improved in vivo knock-down laser photocoagulation mouse model novel novel strategies overexpression prevent programs public health relevance repaired restoration stem cell differentiation

项目摘要

DESCRIPTION (provided by applicant): Glaucoma is a leading cause of irreversible blindness throughout the world and the second leading cause of blindness overall in the USA. Elevated intraocular pressure (IOP) and aging are the most important risk factors for most forms of glaucoma. IOP level is highly dependent on the rate at which the aqueous humor is filtered through the conventional outflow pathway including the trabecular meshwork (TM). Reduced cellularity within the TM and abnormal extracellular matrix (ECM) turnover occur in glaucomatous conditions and correlate with increased outflow resistance and elevated IOP. The goal of this project is to define the mechanisms of stem cell homing and engrafting to the TM tissue, stimulating regeneration of the TM tissue, and hence restoring outflow facility and reducing IOP. In advance of this project, we have already isolated and characterized trabecular meshwork stem cells (TMSCs) from human and mouse TM tissues. These stem cells are multipotent with the abilities to differentiate into phagocytic TM cells and to home to the normal mouse TM tissue after intracameral injection. They can home and engraft to the TM region damaged by laser photocoagulation. This project is designed to test specific hypotheses about the mechanisms of TMSC homing and engrafting as well as remodeling pathological ECM of the TM for TM regeneration. Specific Aim 1 tests the hypothesis that TMSCs home and engraft to the TM tissue via specific chemokines. We will test the role of CXCR4/CXCL12 axis by knockdown or overexpression of these genes in TMSCs and TM cells. Specific Aim 2 tests the hypothesis that engrafted exogenous TMSCs can reconstruct the trabecular meshwork ECM and thus improve aqueous outflow to reduce IOP. We will test the ability of TMSCs to degrade abnormal collagens and to secrete organized ECM in vitro and in vivo. The scientific impact of this study will be the elucidation of the cellular and molecular mechanisms of regeneration potential of the TM by stem cells. The results may also directly lead to the design of stem cell-based therapy or adjunctive treatments that prevent blindness from glaucoma.

描述（由申请人提供）：青光眼是全世界不可逆性失明的主要原因，也是美国总体失明的第二大原因。眼内压升高（IOP）和衰老是大多数青光眼的最重要的危险因素。 IOP 水平高度依赖于房水通过传统流出途径（包括小梁网 (TM)）过滤的速率。TM 内细胞结构减少和异常。细胞外基质 (ECM) 更新发生在青光眼病症中，并与流出阻力增加和眼压升高相关，该项目的目标是确定干细胞归巢和移植到 TM 组织、刺激 TM 组织再生的机制。恢复流出设施并降低眼压在该项目之前，我们已经从人和小鼠 TM 组织中分离和鉴定了小梁网干细胞 (TMSC)，这些干细胞具有多能性。具有分化为吞噬性 TM 细胞并在前房内注射后归巢到正常小鼠 TM 组织的能力。该项目旨在测试有关 TMSC 归巢和移植机制的具体假设。以及重塑 TM 的病理性 ECM 以实现 TM 再生。我们测试了 TMSC 通过特定趋化因子归巢并移植到 TM 组织的假设。将通过在 TMSC 和 TM 细胞中敲低或过度表达这些基因来测试 CXCR4/CXCL12 轴的作用，具体目标 2 测试了雕刻的外源 TMSC 可以重建小梁网 ECM 从而改善房水流出以降低 IOP 的假设。 TMSCs 在体外和体内降解异常胶原蛋白和分泌有组织的 ECM 的能力，这项研究的科学影响将是阐明这一现象。干细胞的 TM 再生潜力的细胞和分子机制这些结果也可能直接导致基于干细胞的疗法或预防青光眼失明的辅助疗法的设计。