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: 7934370
• 负责人: Yan Chen
• 金额: $ 8.44万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7934370
• 关键词: Affect; Age; Age related macular degeneration; Age-Years; Aging; Aging-Related Process; American; Animal Model; Appearance; Atrophic; Autophagocytosis; Autophagosome; 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; public health relevance; research study; response; senescence; subretinal injection

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This project focuses on characterizing a novel signal transduction pathway which may control the aging process of the retina and contribute to age-related macular degeneration (AMD). Results from the studies can potentially be translated into new therapeutic approaches for treating the atrophic form of AMD.

描述（由申请人提供）：申请人研究计划的长期目标是探索与年龄相关的黄斑变性（AMD）（AMD）病因的分子机制并发展基于目标的新型治疗策略。这项K99/R00赠款将促进申请人成为范德比尔特眼科研究所的独立研究人员的过渡，该研究所拥有丰富的科学合作环境，并培养了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，目前仅具有有限的治疗选择。萎缩AMD可能是由于基因/环境相互作用引起的，导致视网膜色素上皮（RPE）进行性变性。衰老是AMD最明确的环境风险因素。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的衰老过程中起关键作用。该假设得到了最近的文献数据的支持，表明MTOR在整合各种环境信号并将其与改变组织功能和生物体的寿命中链接起来起着关键作用。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，我们在此应用中提出了三个具体目标。目的1是确定衰老过程如何调节RPE中的MTOR途径。 AIM 2是确定通过调节自噬的潜在机制调节MTOR信号传导如何在体外影响RPE衰老。 AIM 3是确定MTOR是否使用SOD1基因敲除小鼠在视网膜中形成类似AMD的表型来调节体内RPE的衰老。在指导阶段，申请人将在指导委员会的监督下进行拟议的实验，该委员会由具有AMD病因和发病机理专业知识的导师组成（Paul Sternberg博士），视网膜（David Calkins博士）的神经变性动物模型（David Calkins）和MTOR/AUTOPHAGY（LU BO博士）。委员会的成员将定期开会，监控研究进度，并协助申请人将其职业发展朝着独立发展。 R00阶段的研究将测试与AMD相关的动物模型中MTOR抑制剂的潜在治疗作用。这些研究的结果将提供有关RPE和视网膜老化和与年龄相关的变性的新机械信息。 公共卫生相关性：该项目的重点是表征一种新型的信号转导途径，该途径可能控制视网膜的衰老过程，并有助于与年龄相关的黄斑变性（AMD）。研究的结果可能会被转化为用于治疗AMD萎缩形式的新治疗方法。