Elucidation of the Molecular Mechanisms Driving Genetically-Induced High Myopia

阐明遗传性高度近视的分子机制

基本信息

批准号：
10615170
负责人：
Jefferson James Doyle
金额：
$ 23.75万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615170
关键词：
Aorta Automobile Driving Biochemical Biometry Ciliary Body Clinical Communication Connective Tissue Diseases Data Degenerative Myopia Disease Progression E2F transcription factors Educational workshop Electroretinography Etiology Eye Funding Fundus photography Future Gene Expression Genetic Diseases Goals Growth Histologic Human Immunofluorescence Immunologic Individual Inherited K-Series Research Career Programs Knowledge Laboratories Leadership Length Lung MAPK3 gene Marfan Syndrome Mediating Mendelian disorder Mentors Mentorship Mitogen-Activated Protein Kinases Modeling Molecular Mus Muscle Myopia Optical Coherence Tomography Pathogenesis Pathway interactions Patients Phenotype Photoreceptors Research Research Activity Retina Retinal Degeneration Retinal Detachment Retinal Dystrophy Retinitis Pigmentosa Retinoschisis Review Literature Risk Role Scientist Signal Transduction Techniques Testing Therapeutic Thinness Training Transforming Growth Factor beta Vision Visual impairment Western Blotting Writing autosome bone efficacious treatment experience in vivo inhibitor loss of function mutation meetings mouse model new therapeutic target novel therapeutic intervention p38 Mitogen Activated Protein Kinase programs response responsible research conduct side effect skills

项目摘要

ABSTRACT The goal of this K08 Mentored Clinical Scientist Research Career Development Award application is to provide the candidate with advanced skills needed to establish an independent research program investigating the pathogenesis and therapeutics of monogenic high myopia (HM) and inherited retinal dystrophies (IRDs). Our overall hypothesis is that increased TGFβ signaling drives HM progression and structural changes in the posterior segment indicative of pathological myopia (PM) in Marfan syndrome (MFS) and Rbp3-mediated retinitis pigmentosa (RP). To test this hypothesis, the specific aims are to: 1) Determine the extent that Smad2/3 activation contributes to myopia progression, PM changes and retinal degeneration in MFS and Rbp3-/- mice; 2) Define a role for TGFβ-dependent MAPK activation in myopia progression, PM changes and retinal degeneration in MFS and Rbp3-/- mice. This is based on an extensive review of the literature and our high-quality preliminary data demonstrating that: 1) MFS mice have significantly greater axial length (AL) and -9D myopic shift compared to WT littermates; 2) MFS mouse eyes show increased Smad2/3 and MAPK (Erk1/2, Jnk1/2, p38) activation in the ciliary body and retina; 3) AL and myopic shift are reduced in MFS mice after Erk inhibition; 4) Smad3-/- mice display shorter AL and a prominent hyperopic shift compared to WT littermates. These data indicate that TGFβ downstream pathways represent novel therapeutic targets for myopia and/or PM in MFS. Prior studies illustrated that loss-of-function mutations in RBP3 cause autosomal recessive RP with HM (-12 to -17D) in humans, while Rbp3-/- mice show markedly increased AL and myopic shift, as well as in-vivo and ex-vivo evidence of progressive retinal degeneration. This offers an opportunity to evaluate a role for TGFβ signaling in this etiologically-distinct form of monogenic myopia, with the goal of identifying and targeting common drivers of disease progression. The candidate is proposing a comprehensive training plan, combining formal coursework, meetings, seminars and workshops overseen by his diverse, experienced mentorship team. His specific training goals include to: 1) Refine his knowledge of in-vivo phenotyping of myopia and PM in mice, encompassing mouse eye biometry, autorefraction, fundus photography and optical coherence tomography (OCT); 2) Develop skills in in- vivo phenotyping of IRDs and their complications in mice, including ERG, OCT, and optomotor response (OMR); 3) Enhance his skills in ex-vivo histopathological and biochemical analysis of mouse myopia and IRD models, including PM changes (e.g. retinal detachment, retinoschisis, posterior staphyloma) and retinal degeneration (e.g. retinal thinning, photoreceptor loss); 4) Acquire management skills to build a successful independent laboratory; 5) Develop leadership skills in collaborative research; 6) Refine his communication and writing skills to successfully apply for R01 funding; 7) Continue training in responsible conduct of research. His training plan will be executed in coordination with the research activities described above. Results from this proposal will be used to develop a future R01 research plan that will facilitate the candidate’s transition to independent research.

抽象的 K08 指导临床科学家研究职业发展奖申请的目标是为候选人提供建立独立研究计划调查所需的高级技能单基因高度近视（HM）和遗传性视网膜营养不良（IRD）的发病机制和治疗。我们的总体假设是 TGFβ 信号传导增强可驱动 HM 进展和结构变化马凡综合征 (MFS) 和 Rbp3 介导的病理性近视 (PM) 后段指标为了检验这一假设，具体目标是： 1) 确定 Smad2/3 的程度。激活会导致 MFS 和 Rbp3-/- 小鼠的近视进展、PM 变化和视网膜变性 2) 确定 TGFβ 依赖性 MAPK 激活在近视进展、PM 变化和视网膜变性中的作用这是基于对文献的广泛回顾和我们的高质量初步研究。数据表明：1) 与 MFS 小鼠相比，MFS 小鼠具有显着更大的眼轴长度 (AL) 和 -9D 近视位移与 WT 同窝小鼠相比；2) MFS 小鼠眼睛显示 Smad2/3 和 MAPK（Erk1/2、Jnk1/2、p38）激活增加睫状体和视网膜；3) Erk 抑制后 MFS 小鼠的 AL 和近视位移减少；4) Smad3-/- 小鼠与 WT 同窝小鼠相比，显示出较短的 AL 和显着的远视偏移。这些数据表明 TGFβ。下游途径代表了 MFS 中近视和/或 PM 的新治疗靶点。 RBP3 的功能丧失突变会导致人类常染色体隐性 RP 伴 HM（-12 至 -17D），而 Rbp3-/- 小鼠表现出 AL 和近视转变显着增加，以及进行性的体内和离体证据这为评估 TGFβ 信号在这种病因学上不同的疾病中的作用提供了机会。单基因近视的形式，目的是识别和针对疾病进展的常见驱动因素。候选人提出了一个全面的培训计划，结合了正式的课程、会议、由他的多元化、经验丰富的导师团队监督的研讨会和讲习班他的具体培训目标。包括：1) 完善小鼠近视和 PM 体内表型分析的知识，包括小鼠眼睛生物测量、自动验光、眼底摄影和光学相干断层扫描 (OCT) 2) 培养以下方面的技能：小鼠 IRD 及其并发症的体内表型分析，包括 ERG、OCT 和视运动反应 (OMR)； 3) 增强小鼠近视和IRD模型离体组织病理学和生化分析的技能，包括 PM 变化（例如视网膜脱离、视网膜劈裂、后葡萄肿）和视网膜变性（例如视网膜变薄、感光细胞丧失）；4）获得管理技能以建立成功的独立性实验室；5) 培养协作研究的领导能力；6) 提高沟通和写作能力成功申请 R01 资助； 7) 继续开展负责任的研究培训。将与上述研究活动协调执行。用于制定未来的 R01 研究计划，以促进候选人过渡到独立研究。