Suppressing thyroid hormone signaling to protect cones in retinal degeneration
抑制甲状腺激素信号传导以保护视网膜变性中的视锥细胞
基本信息
- 批准号:8934121
- 负责人:
- 金额:$ 18.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-30 至 2017-09-29
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAge related macular degenerationApoptosisBlindnessCell ProliferationCessation of lifeColor VisionsConeData ReportingDiiodothyroninesDiseaseElderlyEnzymesGenerationsGenesGoalsHealthHeterogeneityImpairmentIndividualInheritedIodothyronine DeiodinaseLeadLeber&aposs amaurosisLightMediatingModelingMusMutationOpsinOutcomePathogenesisPatternPharmaceutical PreparationsPhotoreceptorsPlayPopulationRetinaRetinal ConeRetinal DegenerationRetinal DiseasesRetinitis PigmentosaRoleSignal TransductionTestingThyroid GlandThyroid Hormone ReceptorThyroid HormonesThyrotropinTissuesTransgenesTriiodothyronineViralVisionVision DisordersVisual Acuityachromatopsiaagedbasemouse modelnoveloverexpressionphotoreceptor degenerationpreventreceptorresponsetreatment effect
项目摘要
DESCRIPTION (provided by applicant): Inherited retinal degenerative diseases such as retinitis pigmentosa and cone-rod dystrophies affect approximately one in 3,000 individuals worldwide. Age-related macular degeneration is the leading cause of blindness among the elderly. Despite a remarkable heterogeneity of disease-causing genes and pathogenesis, it is the progressive death of cone photoreceptors that ultimately leads to vision impairment and blindness. There is currently no treatment available for retinal degeneration. Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and apoptosis. In the retina, TH signaling plays a central role in cone opsin expression and patterning. Using several retinal degeneration mouse models, our preliminary studies showed that TH signaling affects cone viability. Suppressing TH signaling (by anti-thyroid treatment) preserves cones and stimulating TH signaling (by thyroid hormone T3 treatment) deteriorates cones. TH signaling in local tissue is primarily regulated via TH receptor (ThR) and the enzyme that inactivates T3, type 3 iodothyronine deiodinase (DIO3). The objective of this study is to determine if suppressing TH signaling locally in the retina preserves cones. We propose two specific aims to address the question. The first aim is to determine whether blocking ThR in the retina preserves cones in retinal degeneration model mice. Rpe65-/-, a model of Leber congenital amaurosis, and cpfl1, a model of achromatopsia, mice will be treated with ThR antagonists via ocular delivery, and cone survival will be evaluated following drug administration. Cone survival will also be evaluated in Rpe65-/- and cpfl1 mice lacking ThR� (cones express � type of ThR, Rpe65-/-/Thr�-/- and cpfl1/Thr�-/-) to determine whether cones are preserved when ThR� is absent. The second aim is to determine whether enhancing expression/function of DIO3 in the retina preserves cones. We will overexpress DIO3 in the retinas of Rpe65-/- and cpfl1 mice through adeno-associated viral (AAV) mediated transgene delivery. Cone survival will be evaluated following transgene delivery. Completion of the proposed study will determine whether suppressing TH signaling locally in the retina preserves cones in retinal degeneration. Specifically, it will establish wheter blocking ThR and overexpressing/activating DIO3 in the retina protects cones. We anticipate an outcome that will lead to a novel and substantially different approach for retinal degeneration management.
描述(由申请人提供):遗传性视网膜退行性疾病,如色素性视网膜炎和锥杆营养不良症,全世界大约每3000人中就有1人受到影响。年龄相关性黄斑变性是老年人失明的主要原因。尽管致病基因和发病机制具有显著的异质性,但最终导致视力障碍和失明的是锥体光感受器的进行性死亡。目前还没有治疗视网膜变性的方法。甲状腺激素(TH)信号传导调节细胞增殖、分化和凋亡。在视网膜中,TH信号在视锥蛋白的表达和模式中起着核心作用。使用几种视网膜变性小鼠模型,我们的初步研究表明TH信号影响视锥细胞的活力。抑制TH信号(通过抗甲状腺治疗)可以保存锥体,而刺激TH信号(通过甲状腺激素T3治疗)会使锥体恶化。局部组织中的TH信号主要通过TH受体(ThR)和3型碘甲状腺原氨酸脱碘酶(DIO3)灭活T3来调节。本研究的目的是确定在视网膜局部抑制TH信号是否保留视锥细胞。我们提出两个具体目标来解决这个问题。第一个目的是确定阻断视网膜中的ThR是否保留视网膜变性模型小鼠的视锥细胞。Rpe65-/- (Leber先天性黑朦模型)和cpfl1(色盲模型)小鼠将通过眼部给药给予ThR拮抗剂治疗,并在给药后评估锥体存活。我们还将在缺乏ThR的Rpe65-/-和cpfl1小鼠(视锥细胞表达ThR类型,Rpe65-/-/ ThR - -和cpfl1/ ThR - -/-)中评估视锥细胞的存活,以确定当ThR -缺失时视锥细胞是否保留。第二个目的是确定增强视网膜中DIO3的表达/功能是否保留视锥细胞。我们将通过腺相关病毒(AAV)介导的转基因传递在Rpe65-/-和cpfl1小鼠的视网膜中过表达DIO3。将在转基因交付后评估锥体存活。该研究的完成将确定在视网膜局部抑制TH信号是否保留视网膜变性中的视锥细胞。具体来说,它将确定阻断ThR和过度表达/激活视网膜中的DIO3是否能保护视锥细胞。我们预期的结果将导致一种新的和实质上不同的视网膜变性管理方法。
项目成果
期刊论文数量(1)
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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{{ truncateString('XI-QIN DING', 18)}}的其他基金
Thyroid Hormone Signaling and Cone Photoreceptor Degeneration
甲状腺激素信号传导和视锥细胞变性
- 批准号:
10686291 - 财政年份:2022
- 资助金额:
$ 18.13万 - 项目类别:
The Role of Endoplasmic Reticulum Calcium Channels in Cone Degeneration Resulting from CNG Channel Deficiency
内质网钙通道在 CNG 通道缺陷导致的视锥细胞变性中的作用
- 批准号:
9286397 - 财政年份:2017
- 资助金额:
$ 18.13万 - 项目类别:
Suppressing thyroid hormone signaling to protect cones in retinal degeneration
抑制甲状腺激素信号传导以保护视网膜变性中的视锥细胞
- 批准号:
8749867 - 财政年份:2014
- 资助金额:
$ 18.13万 - 项目类别:
Mechanism of Cone Degeneration Resulting from CNG Channel Deficiency
CNG通道缺陷导致锥体退化的机制
- 批准号:
8485614 - 财政年份:2010
- 资助金额:
$ 18.13万 - 项目类别:
Mechanism of Cone Degeneration Resulting from CNG Channel Deficiency
CNG通道缺陷导致锥体退化的机制
- 批准号:
8678926 - 财政年份:2010
- 资助金额:
$ 18.13万 - 项目类别:
Mechanism of Cone Degeneration Resulting from CNG Channel Deficiency
CNG通道缺陷导致锥体退化的机制
- 批准号:
8117494 - 财政年份:2010
- 资助金额:
$ 18.13万 - 项目类别:
STRUCTURE AND FUNCTION RELATIONSHIP OF CONE CYCLIC NUCLEOTIDE-GATED CHANNEL
锥环核苷酸门控通道的结构和功能关系
- 批准号:
8168352 - 财政年份:2010
- 资助金额:
$ 18.13万 - 项目类别:
Mechanism of Cone Degeneration Resulting from CNG Channel Deficiency
CNG通道缺陷导致锥体退化的机制
- 批准号:
7985216 - 财政年份:2010
- 资助金额:
$ 18.13万 - 项目类别:
Mechanism of Cone Degeneration Resulting from CNG Channel Deficiency
CNG通道缺陷导致锥体退化的机制
- 批准号:
8301722 - 财政年份:2010
- 资助金额:
$ 18.13万 - 项目类别:
STRUCTURE AND FUNCTION RELATIONSHIP OF CONE CYCLIC NUCLEOTIDE-GATED CHANNEL
锥环核苷酸门控通道的结构和功能关系
- 批准号:
7959979 - 财政年份:2009
- 资助金额:
$ 18.13万 - 项目类别:
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