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:
- 金额:$ 23.75万
- 依托单位:
- 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:
- 关键词:AortaAutomobile DrivingBiochemicalBiometryCiliary BodyClinicalCommunicationConnective Tissue DiseasesDataDegenerative MyopiaDisease ProgressionE2F transcription factorsEducational workshopElectroretinographyEtiologyEyeFundingFundus photographyFutureGene ExpressionGenetic DiseasesGoalsGrowthHistologicHumanImmunofluorescence ImmunologicIndividualInheritedK-Series Research Career ProgramsKnowledgeLaboratoriesLeadershipLengthLungMAPK3 geneMarfan SyndromeMediatingMendelian disorderMentorsMentorshipMitogen-Activated Protein KinasesModelingMolecularMusMuscleMyopiaOptical Coherence TomographyPathogenesisPathway interactionsPatientsPhenotypePhotoreceptorsResearchResearch ActivityRetinaRetinal DegenerationRetinal DetachmentRetinal DystrophyRetinitis PigmentosaRetinoschisisReview LiteratureRiskRoleScientistSignal TransductionTechniquesTestingTherapeuticThinnessTrainingTransforming Growth Factor betaVisionVisual impairmentWestern BlottingWritingautosomeboneefficacious treatmentexperiencein vivoinhibitorloss of function mutationmeetingsmouse modelnew therapeutic targetnovel therapeutic interventionp38 Mitogen Activated Protein Kinaseprogramsresponseresponsible research conductside effectskills
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.
摘要
这个K 08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(IRDs)的发病机制和治疗。
我们的总体假设是,增加TGFβ信号驱动HM进展和结构变化
在马凡氏综合征(MFS)和Rbp 3介导的病理性近视(PM)的后段中,
视网膜色素变性(RP)。为了验证这一假设,具体的目的是:1)确定Smad 2/3
激活有助于MFS和Rbp 3-/-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
在MFS和Rbp 3-/-小鼠中。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)MFS小鼠具有显著更大的眼轴长度(AL)和-9D近视移位,
2)MFS小鼠眼睛显示增加的Smad 2/3和MAPK(Erk 1/2,JNk 1/2,p38)活化,
睫状体和视网膜; 3)在Erk抑制后,MFS小鼠的AL和近视移位减少; 4)Smad 3-/-小鼠
与WT同窝仔相比,显示较短的AL和显著的远视移位。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。先前的研究表明,
RBP 3的功能缺失突变导致人类常染色体隐性RP伴HM(-12至-17 D),而
Rbp 3-/-小鼠显示出显著增加的AL和近视移位,以及体内和离体的进行性近视的证据。
视网膜变性这提供了一个机会,以评估TGFβ信号转导在这种病因学上不同的作用。
单基因近视的形式,目的是识别和靶向疾病进展的共同驱动因素。
候选人提出一个全面的培训计划,结合正式的课程,会议,
由他多元化、经验丰富的导师团队监督的研讨会和研讨会。他的具体训练目标
包括:1)完善他对小鼠近视和PM体内表型分析的知识,包括小鼠眼睛
生物测量、自动验光、眼底照相和光学相干断层扫描(OCT); 2)培养在
IRD的体内表型及其在小鼠中的并发症,包括ERG、OCT和视动反应(OMR);
3)提高他在小鼠近视和IRD模型的离体组织病理学和生化分析方面的技能,
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
(e.g.视网膜变薄,感光细胞丧失); 4)获得管理技能,以建立一个成功的独立
实验室; 5)发展合作研究的领导技能; 6)完善他的沟通和写作技巧
成功申请R 01资助; 7)继续进行负责任的研究行为的培训。他的训练计划
将与上述研究活动协调执行。该提案的结果将是
用于制定未来的R 01研究计划,以促进候选人向独立研究的过渡。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jefferson James Doyle其他文献
Jefferson James Doyle的其他文献
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{{ truncateString('Jefferson James Doyle', 18)}}的其他基金
Elucidation of the Molecular Mechanisms Driving Genetically-Induced High Myopia
阐明遗传性高度近视的分子机制
- 批准号:
10429430 - 财政年份:2022
- 资助金额:
$ 23.75万 - 项目类别:
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