mTOR-mediated Signaling Pathway in Aging of the Retinal Pigment Epithelium

mTOR 介导的视网膜色素上皮老化信号通路

• 批准号: 8541858
• 负责人: Yan Chen
• 金额: $ 23.28万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8541858
• 关键词: Affect; Age related macular degeneration; Age-Years; Aging; Aging-Related Process; American; Animal Model; Appearance; Atrophic; Autophagocytosis; Autophagosome; Basic Science; Biochemical; Blindness; Bruch' s basal membrane structure; Cells; Characteristics; Chronic; Clinical Research; Clinical Trials; Collaborations; Committee Members; Complex; Data; Degenerative Disorder; Development; Disease; Drusen; Elderly; Ensure; Environment; Environmental Risk Factor; Etiology; Event; Eye; Functional disorder; Genes; Goals; Grant; Growth; Growth Factor; Histology; Human; In Vitro; Individual; Institutes; Knockout Mice; Lead; Legal Blindness; Link; Lipofuscin; Literature; Longevity; Malignant Neoplasms; Mammalian Cell; Measures; Mediating; Mentors; Methods; Molecular; Monitor; Mus; Nerve Degeneration; Nonexudative age-related macular degeneration; Nutrient; Organelles; Organism; Pathogenesis; Pathology; Pathway interactions; Patients; Phase; Phenotype; Play; Proteins; RNA Splicing; Raptors; Reporting; Research; Research Personnel; Retina; Retinal Degeneration; Risk; Rodent; Role; Scientist; Secondary to; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Sirolimus; Small Interfering RNA; Staging; Structure of retinal pigment epithelium; Supervision; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Training; Translating; Variant; age related; aged; base; career; career development; gene delivery system; gene environment interaction; human disease; in vivo; inhibitor/antagonist; knock-down; mTOR protein; meetings; neovascular; novel; novel therapeutic intervention; overexpression; programs; protein degradation; research study; response; senescence; subretinal injection

PROJECT SUMMARY The long term goal of the Applicant's research program is to explore the molecular mechanisms underlying the etiology of age-related macular degeneration (AMD) and develop novel target-based therapeutic strategies. This K99/R00 grant will facilitate the transition for the Applicant to become an independent investigator at the Vanderbilt Eye Institute, which has a rich environment of scientific collaboration and nurturing career development of junior scientists. AMD is the leading cause of blindness in elderly Americans. The majority of AMD patients has atrophic (dry) form of the disease and has only limited treatment options at the present time. Atrophic AMD is likely resulted from gene/environmental interaction causing progressive degeneration of the retinal pigment epithelium (RPE). Aging is the most well defined environmental risk factor of AMD. We hypothesize that the mammalian target of rapamycin (mTOR)-mediated signaling pathway plays key roles in controlling the aging process of the RPE. The hypothesis is supported by recent literature data suggesting that mTOR plays key roles in integrating various environmental signals and linking them to altered tissue function and organism's life span. In our preliminary studies, we found that rapamycin reversed the senescent phenotype of primary human RPE cells in vitro. To further test our hypothesis, we have proposed three specific aims in this application. Aim 1 is to determine how the aging process regulates mTOR pathways in the RPE. Aim 2 is to determine how modulating the mTOR signaling affects RPE aging in vitro by a potential mechanism of regulating autophagy. Aim 3 is to determine whether mTOR regulates aging of the RPE in vivo using SOD1 knockout mice which develop AMD-like phenotype in the retina. During the mentored phase, the Applicant will conduct the proposed experiments under the supervision of a mentoring committee, which is consisted of mentors with expertise in AMD etiology and pathogenesis (Dr. Paul Sternberg), animal models of neurodegeneration in the retina (Dr. David Calkins) and mTOR/autophagy (Dr. Lu Bo). Members of the committee will meet regularly, monitor the research progress and assist the Applicant to advance her career towards independence. Research at the R00 phase will test the potential therapeutic effects of mTOR inhibitors in an animal model relevant to AMD. Results from these studies will provide novel mechanistic information on aging and age-related degeneration of the RPE and retina.

项目摘要 申请人研究计划的长期目标是探索分子机制 与年龄相关的黄斑变性（AMD）的病因基础，并发展基于目标的基于目标的治疗 策略。此K99/R00赠款将有助于申请人成为独立的过渡 范德比尔特眼科研究所的调查员，该研究所拥有丰富的科学合作环境 培养初级科学家的职业发展。 AMD是美国老年人失明的主要原因。 大多数AMD患者患有疾病的萎缩性（干）形式，仅在治疗方案有限 现在的时间。萎缩AMD可能是由于基因/环境相互作用引起的 视网膜色素上皮（RPE）的变性。衰老是最明确的环境风险因素 AMD。我们假设雷帕霉素的哺乳动物靶标（MTOR）介导的信号通路 在控制RPE的老化过程中起关键作用。该假设得到了最近的支持 文献数据表明，MTOR在整合各种环境信号和链接中起关键作用 它们改变了组织功能和生物的寿命。在我们的初步研究中，我们发现雷帕霉素 在体外逆转了原代人RPE细胞的衰老表型。为了进一步检验我们的假设，我们 在此应用程序中提出了三个具体目标。目标1是确定衰老过程如何调节 RPE中的mtor途径。 AIM 2是确定调节MTOR信号如何影响RPE老化 通过调节自噬的潜在机制的体外。 AIM 3是确定MTOR是否调节衰老 使用SOD1基因敲除小鼠在体内的RPE，该小鼠在视网膜中形成了类似AMD的表型。在 指导阶段，申请人将在指导的监督下进行拟议的实验 委员会由具有AMD病因和发病机理专业知识的导师组成（Paul博士 Sternberg），视网膜（David Calkins博士）和MTOR/自噬的动物模型（博士 lu bo）。委员会成员将定期开会，监视研究进度并协助申请人 向独立发展她的职业生涯。 R00阶段的研究将测试潜在的治疗 MTOR抑制剂在与AMD相关的动物模型中的影响。这些研究的结果将提供新颖 RPE和视网膜的衰老和年龄相关变性的机械信息。