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.

项目摘要 青光眼是全世界不可逆失明的主要原因，也是第二个主要原因 美国总体失明。眼内压（IOP）和衰老是最重要的危险因素 对于大多数形式的青光眼。 IOP级别高度取决于过滤水性幽默的速度 通过包含小梁网（TM）的传统出口通路。降低的细胞内 TM和异常细胞外基质（ECM）周转率发生在青光眼条件下，并与 增加输出电阻，IOP升高以及随后的视力丧失。该项目的目的是定义 干细胞寄养和向TM组织的机制，激活TM组织的再生和 因此，恢复出口设施，减少IOP并防止视力丧失。在我们以前的资金期间，我们 已经确定了干细胞归巢和整合的机制，部分与CXCR4/SDF1有关 趋化因子对和α5β1整合素。我们还确认了TM干细胞（TMSC），在体内 注射，可以再生TM组织，减少IOP并保留小鼠的视网膜神经节细胞功能 青光眼模型。该项目旨在测试有关人类的机制的特定假设 TMSC重塑病理TM组织并恢复TM功能。特定目标1检验假设 TMSC和分化的TM细胞通过COX2/PGE2/MMP途径重塑了绝对TM ECM。 我们将利用肌动蛋白突变体TM细胞和地塞米松处理的TM细胞以及小鼠青光眼 具有肌动蛋白突变的模型，以测试TMSC如何促进ECM营业额并修改TM节段 流出模式。特定的目标2检验了移植TMSC可以促进内源性的假设 通过SOX21/WNT信号传导TMSC激活，迁移和功能。如果内源性，我们将公布 TMSC是可行的，在人类和小鼠中的老年和青光眼TM组织中，数量降低 发现TMSC如何通过SOX21/WNT信号唤醒内源性TMSC。这项研究的科学影响 将是干细胞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疗法或辅助治疗 在临床上预防青光眼失明。