Mechanisms of Trabecular Meshwork Regeneration by Stem Cells

干细胞小梁网再生机制

• 批准号: 10895151
• 负责人: Yiqin Du
• 金额: $ 45.68万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10895151
• 关键词: Address; Aging; Aqueous Humor; Blindness; CRISPR/Cas technology; CXCR4 gene; Cell Survival; Cell physiology; Cells; Cellularity; Characteristics; Clinical; Cornea; Data; Deposition; Dexamethasone; Dinoprostone; Engraftment; Extracellular Matrix; Foundations; Funding; Glaucoma; Goals; Home; Homeostasis; Homing; Human; Impairment; In Vitro; Injections; Integrin alpha5beta1; Lead; Longevity; Matrix Metalloproteinases; Modeling; Molecular; Mus; Mutation; Natural regeneration; Operative Surgical Procedures; Optic Nerve; PTGS2 gene; Pathologic; Pathway interactions; Patient Noncompliance; Pattern; Pharmaceutical Preparations; Phenotype; Physiologic Intraocular Pressure; Rejuvenation; Resistance; Retinal Ganglion Cells; Risk Factors; SOX21 gene; Site; Solid; Source; Stem cell transplant; Stromal Cell-Derived Factor 1; Testing; Therapeutic; Tissues; Trabecular meshwork structure; Transgenes; Transplantation; Treatment Efficacy; WNT Signaling Pathway; Work; adipose derived stem cell; aged; aqueous; awake; chemokine; clinical application; clinical translation; design; effective therapy; experimental study; in vivo; in vivo Model; inhibitor; laser photocoagulation; migration; mouse genetics; mutant; myocilin; nerve damage; preservation; prevent; regeneration potential; repaired; restoration; self-renewal; side effect; stem cell proliferation; stem cell self renewal; stem cell therapy; stem cells; transcriptome sequencing

Project Summary 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 containing 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, elevated IOP, and subsequent vision loss. The goal of this project is to define the mechanisms of stem cell homing and engrafting to the TM tissue, activating regeneration of the TM tissue, and hence restoring outflow facility, reducing IOP, and preventing vision loss. In our previous funding period, we have identified the mechanisms of stem cell homing and integration are partially associated with CXCR4/SDF1 chemokine pair and α5β1 integrin. We have also confirmed that TM stem cells (TMSCs), after intracamerally injection, can regenerate the TM tissue, reduce IOP, and preserve the retinal ganglion cell function in a mouse glaucoma model. This project is designed to test specific hypotheses about the mechanisms by which human TMSCs remodel the pathological TM tissue and restore the TM function. Specific Aim 1 tests the hypothesis that TMSCs and differentiated TM cells remodel the abnormal TM ECM via the COX2/PGE2/MMP pathway. We will utilize myocilin mutant TM cells and dexamethasone-treated TM cells as well as a mouse glaucoma model with myocilin mutation to test how TMSCs promote the ECM turnover and modify the TM segmental outflow pattern. Specific Aim 2 tests the hypothesis that transplanted TMSCs can promote endogenous TMSC activation, migration, and function via the SOX21/WNT signaling. We will unveil if the endogenous TMSCs are viable with a reduced number in aged and glaucomatous TM tissue in human and in mice and uncover how TMSCs awake endogenous TMSCs via SOX21/WNT signaling. The scientific impact of this study will be the elucidation of the cellular and molecular mechanisms of TM regeneration potential by stem cells. The results may also directly lead to the design of stem cell-based therapies or adjunctive treatments that prevent blindness from glaucoma clinically.

项目概要 青光眼是全世界不可逆性失明的主要原因，也是导致失明的第二大原因 在美国，眼压（IOP）升高和衰老是最重要的风险因素。 对于大多数类型的青光眼，眼压水平高度依赖于房水的过滤速度。 通过包含小梁网 (TM) 的传统流出途径。 TM 和异常细胞外基质 (ECM) 周转发生在青光眼病症中，并与 流出阻力增加、眼压升高以及随后的视力丧失。该项目的目标是定义 干细胞归巢和移植到TM组织、激活TM组织再生的机制，以及 因此，在我们之前的资助期间，我们恢复了流出设施，降低了眼压，并防止视力丧失。 已经确定干细胞归巢和整合的机制部分与 CXCR4/SDF1 有关 我们还证实了TM干细胞（TMSCs）在前房内注射后具有趋化因子对和α5β1整合素。 注射，可以再生TM组织，降低眼压，并保留小鼠视网膜神经节细胞功能 该项目旨在测试有关人类机制的具体假设。 TMSC 重塑病理性 TM 组织并恢复 TM 功能特定目标 1 检验假设。 TMSCs和分化的TM细胞通过COX2/PGE2/MMP途径重塑异常的TM ECM。 我们将利用 myocilin 突变 TM 细胞和地塞米松处理的 TM 细胞以及小鼠青光眼 肌纤蛋白突变模型，测试 TMSC 如何促进 ECM 更新并修改 TM 节段 具体目标 2 检验移植的 TMSC 可以促进内源性的假设。 我们将通过 SOX21/WNT 信号传导来揭示 TMSC 的激活、迁移和功能。 TMSCs 在人类和小鼠的衰老和青光眼 TM 组织中具有活力，且数量减少，并且 揭示 TMSC 如何通过 SOX21/WNT 信号传导唤醒内源性 TMSC 本研究的科学影响。 将阐明干细胞TM再生潜力的细胞和分子机制。 研究结果还可能直接导致基于干细胞的疗法或辅助疗法的设计 临床上可预防青光眼致盲。