Role in Myopia Development of Retinal Pigment Epithelium - A New Therapeutic Targ

视网膜色素上皮在近视发展中的作用——一种新的治疗目标

• 批准号: 8568409
• 负责人: Yan Zhang
• 金额: $ 14.97万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8568409
• 关键词: Academia; Affect; Animal Model; Animals; Apical; Apomorphine; Award; Blood; Bone Morphogenetic Protein Gene; Bone Morphogenetic Proteins; California; Cell Culture Techniques; Cell Differentiation process; Cells; Cellular biology; Choroid; Clinical; Cloning; Communities; Data; Development; Developmental Biology; Discipline; Disease; Doctor of Philosophy; Dopamine; Dopamine Agonists; Electrophysiology (science); Electroporation; Electroretinography; Embryonic Development; Environment; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Eye; Eye diseases; Family; Frequencies; Funding; Gene Expression; Genes; Goals; Grant; Growth; Growth Factor; Harvest; Human; Image; Immunohistochemistry; In Vitro; Individual; Investigation; Journals; K-Series Research Career Programs; Knowledge; Measurement; Measures; Mediating; Medicine; Mentors; Mentorship; Modeling; Molecular Biology; Morphogenesis; Myopia; Ophthalmology; Optic Nerve; Optical Coherence Tomography; Optics; Outcome; Paper; Physiology; Play; Population; Positioning Attribute; Preparation; Prevalence; Production; Productivity; Protein Family; Protein Secretion; Publications; Refractive Errors; Regulation; Research; Research Personnel; Research Proposals; Retina; Retinal; Risk; Role; San Francisco; Scanning; Scientist; Senior Scientist; Severities; Signal Transduction; Structure of retinal pigment epithelium; Techniques; Technology; Testing; Therapeutic Intervention; Therapeutic Studies; Time; Tissues; Training; Translational Research; Ultrasonography; United States National Institutes of Health; Universities; Virus; Western Blotting; age group; bone; bone morphogenetic protein 2; career; career development; economic implication; experience; fetal; follow-up; gene therapy; immunocytochemistry; in vitro Model; in vivo; knock-down; lens; member; new therapeutic target; novel; novel therapeutics; prevent; professor; programs; protein expression; public health relevance; receptor; research study; response; skills; social implication; subretinal injection; vision science

Zhang Y. Role in Myopia Development of Retinal Pigment Epithelium - A New Therapeutic Target ? Project Summary The Mentored Clinical Scientist Research Career Development Award (K08) candidate, Yan Zhang, earned her clinical degrees in Medicine and Ophthalmology, and she is currently pursuing her Ph.D. degree in the Vision Science Program at University of California, Berkeley, which will be completed in the Spring 2013. She has already one publication in a high profile journal from the latter research, with 2 more papers soon to be submitted, demonstrating both good productivity and research drive. As the next step towards a career as an independent clinician scientist in academia, Dr. Zhang is applying for a K08 career award to obtain advanced training - to further expand her scientific knowledge and biomedical technical skills through investigations into the roles of retinal pigment epithelium (RPE) and bone morphogenetic proteins (BMPs) in eye growth regulation and myopia development, with the RPE targeted in related exploratory studies of gene therapy for myopia treatment. Over the course of her studies to-date, Dr. Zhang has received broad training in many of the disciplines required for successfully executing her proposed project. She proposed to cover remaining deficiencies with additional coursework and hands-on training during the 5-year training period of the K award for which she is applying. Thus at the end of this 5-year career development award Dr. Zhang should be well prepared for a career as an independent researcher, successfully competing for research funds. The proposed study will be conducted primarily under the mentorship of Dr. Christine Wildsoet, who is a well- known leading scientist in the field of myopia and eye growth regulation. Myopia, or nearsightedness, is one of most common refractive errors in humans and significantly contributes to the global burden of eye disease. It is the product of eyes growing excessively long. The prevalence and the severity of myopia have risen worldwide during the past several decades, stimulating increased research into the underlying mechanisms, an essential step in developing effective anti-myopia therapies. Previous studies have suggested that early eye growth regulation is largely localized to eye itself. The RPE is known to be a component of the blood-retina barrier, with critical roles in maintaining normal retinal and choroidal functions. Recent research findings, mostly from the Wildsoet lab and much of it belongs to Dr. Zhang, suggest that it also plays an essential role in the regulation of eye growth. The proposal focuses on the role of RPE in myopia development and as a potential target for myopia therapy, with 3 specific aims: (1) to investigate the role of RPE-derived bone morphogenetic proteins (BMPs) in eye growth regulation; (2) to investigate the effects of dopamine (DA) on RPE-BMP expression and secretion; (3) to investigate over-expression of BMPs in RPE as a potential gene therapy for myopia. Complementary experiments include in vivo animal studies, using the chick as an myopia model, and in vitro cell culture studies, using human fetal (hf) RPE as a model, exploiting Dr. Zhang's experience with both models. In vivo structural and functional measurements will use advanced technologies, including high frequency A-scan ultrasonography, spectral domain optical coherence tomography (SD-OCT) and electroretinography (ERG). A variety of molecular and cell biology techniques will also be used including cloning, real-time PCR, Western blot, ELISA, and immunohistochemistry. Techniques most commonly encountered in ocular gene therapy research, including electroporation and subretinal injection, will also be employed. The proposed research will be conducted under the co-mentorship of Dr. Jeanette Hyer from UC San Francisco, who is an expert in developmental biology, with a focus on chick embryogenesis. Three senior scientists have also agreed to serve as consultants on her project: Professor Lawrence Rizzolo (Yale University) and Dr. Sheldon Miller (NEI/NIH), who are experts in RPE physiology and electrophysiology, and Professor Kunxin Luo (UC Berkeley), whose research focus is the TGF-¿ family including BMPs and their roles in cell differentiation, tissue morphogenesis, and extracellular matrix production. UC Berkeley and UC San Francisco offer world-class research environments and support for the preparation and training of young scientists for independent research careers.

张永视网膜色素上皮细胞在近视发展中的作用--一个新的治疗靶点？ 项目摘要 导师临床科学家研究职业发展奖（K 08）候选人Yan Zhang赢得了她 医学和眼科临床学位，她目前正在攻读博士学位。在视觉上的程度 科学计划在加州大学伯克利分校，这将在2013年春季完成。她有 后者的研究已经在一个高知名度的期刊上发表了一篇论文，不久将发表另外2篇论文。 提交，表现出良好的生产力和研究驱动力。作为职业生涯的下一步， 作为学术界的独立临床科学家，张博士正在申请K 08职业奖，以获得高级 培训-通过调查研究，进一步扩大她的科学知识和生物医学技术技能 视网膜色素上皮（RPE）和骨形态发生蛋白（BMPs）在眼睛生长中的作用 调节和近视发展，与RPE靶向基因治疗的相关探索性研究， 近视治疗在迄今为止的学习过程中，张博士在许多方面接受了广泛的培训， 成功执行其拟议项目所需的纪律。她建议将剩余的 在K的5年培训期间，额外的课程和实践培训的不足之处 她申请的奖项。因此，在这5年的职业发展奖结束时，张博士应该 为独立研究人员的职业生涯做好充分准备，成功地竞争研究资金。的 拟议的研究将主要在克莉丝汀怀尔德索特博士的指导下进行，他是一个很好的- 在近视和眼睛生长调节领域的知名首席科学家。近视是其中之一 是人类最常见的屈光不正之一，是全球眼科疾病负担的重要组成部分。 这是眼睛长得过长的结果。近视的患病率和严重程度有所上升 在过去的几十年里，世界范围内，刺激了对潜在机制的研究， 开发有效的抗近视疗法的重要一步。先前的研究表明， 生长调节主要局限于眼睛本身。已知RPE是血视网膜的组成部分 屏障，在维持正常的视网膜和脉络膜功能中起关键作用。最近的研究发现， 大部分来自Wildsoet实验室，其中大部分属于张博士，这表明它在以下方面也发挥着重要作用 调节眼睛的生长。该提案的重点是RPE在近视发展中的作用， 近视治疗的潜在靶点，有3个具体目标：（1）研究RPE衍生骨的作用 目的：（1）探讨形态发生蛋白（BMP）在眼生长调节中的作用;（2）探讨多巴胺（DA）对眼生长的影响。 RPE-BMP的表达和分泌;（3）探讨BMPs作为一种潜在基因在RPE中的过表达 治疗近视。补充实验包括体内动物研究，用小鸡作为近视眼 模型和体外细胞培养研究，使用人胎儿（hf）RPE作为模型，利用Zhang博士的 这两种模式的经验。体内结构和功能测量将使用先进的技术， 包括高频A扫描超声、谱域光学相干断层扫描（SD-OCT） 和视网膜电图（ERG）。还将使用各种分子和细胞生物学技术，包括 克隆、实时PCR、Western印迹、ELISA和免疫组织化学。最常见的技术 在眼部基因治疗研究中遇到的，包括电穿孔和视网膜下注射，也将是 就业。拟议的研究将在UC的Jeanette Hyer博士的共同指导下进行 San弗朗西斯科，他是发育生物学专家，专注于鸡胚胎发生。三名高级 科学家们也同意为她的项目担任顾问：劳伦斯·里佐洛教授（耶鲁大学） 谢尔顿米勒博士（NEI/NIH），他们是RPE生理学和电生理学的专家， Kunxin Luo（加州大学伯克利分校），其研究重点是TGF-β家族，包括BMP及其在细胞中的作用 分化、组织形态发生和细胞外基质产生。加州大学伯克利分校和加州大学旧金山弗朗西斯科 提供世界一流的研究环境，并支持年轻科学家的准备和培训， 独立研究职业。