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：
9769757
负责人：
Yiqin Du
金额：
$ 39.06万
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 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9769757
关键词：
AMD3100 Address 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 Expression Profiling Extracellular Matrix Extracellular Matrix Degradation Eye Fibronectins Gene Expression Genes Glaucoma Goals Home environment Homeostasis Homing Human In Vitro Injections Lasers Lead Matrix Metalloproteinases Mediating Molecular 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 side effect 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（由适用提供）：青光眼是全世界不可逆转的失明的主要原因，也是美国整体失明的第二大主要原因。眼内压（IOP）和衰老升高是大多数青光眼的最重要危险因素。 IOP水平高度取决于通过包括小梁网（TM）在内的传统出口通路过滤水性幽默的速度。 TM内的细胞性降低和异常的细胞外基质（ECM）周转率在青光眼条件下发生，并且与输出电阻增加和IOP升高相关。该项目的目的是定义干细胞寄养和向TM组织的机理，刺激TM组织的再生，从而恢复输出设施并减少IOP。在该项目之前，我们已经从人和小鼠TM组织分离并表征了小梁网络细胞（TMSC）。这些干细胞具有多功能体，具有分化为吞噬TM细胞的能力，并在室内注射后将其与正常小鼠TM组织的家园。他们可以回家并涉足被激光光凝损坏的TM区域。该项目旨在检验有关TM着色和雕刻机制以及TM再生的TM的病理ECM的特定假设。特定目标1通过特定的趋化因子检验了TMSCS回家和TM组织的假设。我们将通过在TMSC和TM细胞中敲除或过表达CXCR4/CXCL12轴的作用。特定的目标2检验了一个假设，即烧伤的外源TMSC可以重建小梁网ecm，从而改善了降低IOP的水性出口。我们将测试TMSC降解异常胶原蛋白和秘密组织ECM的能力。这项研究的科学影响将是干细胞对TM再生潜力的细胞和分子机制的阐明。结果也可能直接导致设计干细胞的治疗或辅助治疗，以防止青光眼失明。