Stimulating Retina Regeneration from Muller Cells in Progressive Retinal Degenerations
刺激进行性视网膜变性中 Muller 细胞的视网膜再生
基本信息
- 批准号:10379368
- 负责人:
- 金额:$ 51.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:1 year oldAcuteAdultAffectArchitectureBardet-Biedl SyndromeBlindnessCell DeathCell NucleusCellsCessation of lifeChemicalsChronicConeDataDegenerative DisorderDiseaseDisease modelEnvironmentEventExhibitsExposure toFishesFunctional disorderGenesGoalsGrowth FactorHumanImmuneImmunohistochemistryIndividualInflammationInflammatoryInheritedInjuryKnowledgeLeber&aposs amaurosisLightLiteratureMammalsMechanicsMethodsMicrogliaModelingMuller&aposs cellMultipotent Stem CellsMutationNatural regenerationNeuronsPathway interactionsPatientsPersonsPharmacologyPhotoreceptorsPlayProcessProdrugsProliferatingPropertyPublished CommentQuantitative Reverse Transcriptase PCRRegenerative responseReporterRetinaRetinal ConeRetinal DegenerationRetinal DiseasesRetinal DystrophyRetinitis PigmentosaRodRoleSignal PathwaySignal TransductionSourceSystemTestingTherapeuticTimeToxic effectTransgenic OrganismsTranslatingWarZebrafishciliopathycytokinecytotoxicitydensitygenetic approachhuman modelimmunoregulationinherited retinal degenerationmacrophagemouse modelmutantneuron lossnovelnovel strategiesphotoreceptor degenerationprecursor cellprogenitorregeneration potentialresponserestorationretinal damageretinal neuronretinal progenitor cellretinal regenerationretinal rodssight restorationstem cellstissue repairtranscription factortranscriptometranscriptome sequencingtranscriptomicsvirtual
项目摘要
Inherited retinal degenerations (IRDs) result in the progressive and permanent death of neurons. In
recent years, however, our knowledge of endogenous stem cells in the retina has opened the
possibility of stimulating regeneration of lost neurons in patients suffering from IRDs. Leber's
Congenital Amaurosis (LCA), Bardet-Biedl Syndrome, and Retinitis Pigmentosa are among the most
common form of IRDs. Mutations in CEP290 are one of the most common causes of LCA, while
mutations in BBS2 contribute to BBS and mutations in the EYS gene cause RP. We demonstrate
that zebrafish with mutations in the either cep290, bbs2, or eys genes undergo a progressive cone
degeneration with evidence of rod dysfunction. Unlike mammals, zebrafish have the innate ability to
regenerate retinal neurons when they are damaged or lost. In response to retinal injury, zebrafish
exhibit a robust capability of regenerating lost neurons, including photoreceptors. Retinal damage
causes release of growth factors and inflammatory cytokines that trigger Müller glia to divide and
generate multipotent retinal progenitor cells that regenerate lost neurons. Central to this process is a
reprogramming event that involves activation of Stat3. While robust regeneration occurs following
acute injury, evidence from the literature and preliminary data indicate that regeneration does not
occur in zebrafish with inherited forms of retinal degeneration, such as the cep290-/-, bbs2-/-, or eys-/- mutants. These observations suggest that Müller glia respond differently to acute vs. inherited forms
of retinal injury and that regeneration is only triggered when the degree of retinal injury crosses a
“damage threshold” within a temporal window. In zebrafish degeneration mutants there is
widespread proliferation of rod progenitor cells. However, Müller glia, which are the source of cone
progenitors, fail to proliferate. Using what is known about mechanisms involved in regeneration after
acute retinal injury in zebrafish, we will test components of these signaling pathways to determine if
they are activated in Müller cells of these photoreceptor degeneration mutants. In particular, we will
focus on pathways that converge to activate Stat3. Using RNAseq on purified Muller glia from these
degeneration mutants, we will investigate how degeneration and inflammation alter the transcriptome
of Muller glia. Finally, we will use pharmacological and genetic approaches to suppress immune cell
activity and understand the role of microglia and macrophages on degeneration and regeneration.
Understanding the mechanisms that underpin retinal regeneration in multiple zebrafish disease
models will generate novel hypotheses that can ultimately be translated into humans with retinal
degenerative diseases.
遗传性视网膜变性(IRD)导致神经元的进行性和永久性死亡。在
然而,近年来,我们对视网膜中内源性干细胞的了解,
刺激IRD患者丢失的神经元再生的可能性。Leber氏
先天性黑蒙(LCA)、Bardet-Biedl综合征和视网膜色素变性是最常见的
IRD的常见形式。CEP 290突变是LCA最常见的原因之一,
BBS 2的突变导致BBS,EYS基因的突变导致RP。我们证明
cep 290,bbs 2或eys基因突变的斑马鱼经历了一个渐进的圆锥
变性并有视杆功能障碍的证据。与哺乳动物不同,斑马鱼具有先天的能力,
当视网膜神经元受损或丢失时,它们会再生。为了应对视网膜损伤,斑马鱼
表现出再生失去的神经元(包括光感受器)的强大能力。视网膜损伤
引起生长因子和炎症细胞因子的释放,触发Müller神经胶质细胞分裂,
产生再生失去的神经元的多能视网膜祖细胞。这一进程的核心是
涉及Stat 3激活的重编程事件。虽然在以下情况下会发生强劲的再生
急性损伤,来自文献和初步数据的证据表明,再生不
发生在具有遗传形式的视网膜变性的斑马鱼中,例如cep 290-/-、bbs 2-/-或eys-/-突变体。这些观察结果表明,米勒神经胶质细胞对急性与遗传形式的反应不同,
视网膜损伤的程度,只有当视网膜损伤的程度超过了
“损害阈值”在时间窗口内。在斑马鱼退化突变体中,
视杆祖细胞的广泛增殖。然而,Müller胶质细胞,这是锥细胞的来源,
祖细胞无法增殖利用已知的再生机制,
在斑马鱼急性视网膜损伤,我们将测试这些信号通路的组成部分,以确定是否
它们在这些光感受器变性突变体的Müller细胞中被激活。特别是要
聚焦于激活Stat 3的途径。使用RNAseq对来自这些细胞的纯化的Muller神经胶质细胞进行分析,
我们将研究变性和炎症如何改变转录组
Muller胶质细胞。最后,我们将使用药理学和遗传学方法来抑制免疫细胞,
活性,了解小胶质细胞和巨噬细胞在变性和再生中的作用。
了解支持多发性斑马鱼疾病视网膜再生的机制
模型将产生新的假设,这些假设最终可以转化为人类视网膜病变。
退化性疾病
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Brian D Perkins其他文献
Brian D Perkins的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Brian D Perkins', 18)}}的其他基金
Inflammatory Signaling and Regeneration in Zebrafish models of Retinal Degeneration
视网膜变性斑马鱼模型中的炎症信号传导和再生
- 批准号:
10751153 - 财政年份:2023
- 资助金额:
$ 51.01万 - 项目类别:
The Role of Wrb in Vertebrate Ribbon Synapse Formation
Wrb 在脊椎动物带状突触形成中的作用
- 批准号:
8301306 - 财政年份:2012
- 资助金额:
$ 51.01万 - 项目类别:
The Role of Wrb in Vertebrate Ribbon Synapse Formation
Wrb 在脊椎动物带状突触形成中的作用
- 批准号:
8489300 - 财政年份:2012
- 资助金额:
$ 51.01万 - 项目类别:
The Role of Wrb in Vertebrate Ribbon Synapse Formation
Wrb 在脊椎动物带状突触形成中的作用
- 批准号:
8586073 - 财政年份:2012
- 资助金额:
$ 51.01万 - 项目类别:
Cilia Assembly and Transport in the Vertebrate Retina
脊椎动物视网膜中纤毛的组装和运输
- 批准号:
8868294 - 财政年份:2006
- 资助金额:
$ 51.01万 - 项目类别:
Cilia Assembly and Transport in Photoreceptor Cells
感光细胞中纤毛的组装和运输
- 批准号:
8918621 - 财政年份:2006
- 资助金额:
$ 51.01万 - 项目类别:
Cilia Assembly and Transport in the Vertebrate Retina
脊椎动物视网膜中纤毛的组装和运输
- 批准号:
8187542 - 财政年份:2006
- 资助金额:
$ 51.01万 - 项目类别:
Cilia Assembly and Transport in Photoreceptor Cells
感光细胞中纤毛的组装和运输
- 批准号:
10206144 - 财政年份:2006
- 资助金额:
$ 51.01万 - 项目类别:
相似海外基金
Un/kindness, shame & resistance: the care of inpatients in NHS adult acute mental health units and how it might be improved
Un/善良,羞耻
- 批准号:
2885806 - 财政年份:2023
- 资助金额:
$ 51.01万 - 项目类别:
Studentship
Post-Acute Care Transitions for Older Adult Medicare Beneficiaries with Serious Mental Illness
患有严重精神疾病的老年医疗保险受益人的急性后护理过渡
- 批准号:
10772386 - 财政年份:2023
- 资助金额:
$ 51.01万 - 项目类别:
Paving The Way to a Canadian Standard of Care with CAR-T Cellular Therapy: Phase II Trial of CD19 CAR-T for Relapsed/Refractory Adult Acute Lymphoblastic Leukemia (CLIC-01A)
通过 CAR-T 细胞疗法为加拿大护理标准铺平道路:CD19 CAR-T 治疗复发/难治性成人急性淋巴细胞白血病的 II 期试验 (CLIC-01A)
- 批准号:
474619 - 财政年份:2022
- 资助金额:
$ 51.01万 - 项目类别:
Operating Grants
Investigating the impact acute inhalation of cannabis with a high content of delta-9-tetrahydrocannabinol has on myelination and microglia in adult and aged mice
研究急性吸入高含量 delta-9-四氢大麻酚的大麻对成年和老年小鼠髓鞘形成和小胶质细胞的影响
- 批准号:
485965 - 财政年份:2022
- 资助金额:
$ 51.01万 - 项目类别:
Studentship Programs
Paving The Way to a Canadian Standard of Care with CAR-T Cellular Therapy: Phase II Trial of CD19 CAR-T for Relapsed/Refractory Adult Acute Lymphoblastic Leukemia (CLIC-01A)
通过 CAR-T 细胞疗法为加拿大护理标准铺平道路:CD19 CAR-T 治疗复发/难治性成人急性淋巴细胞白血病的 II 期试验 (CLIC-01A)
- 批准号:
466358 - 财政年份:2022
- 资助金额:
$ 51.01万 - 项目类别:
Operating Grants
Metabolomics for prediction of cisplatin mediated acute kidney injury: a Canadian multi-centre adult and pediatric study
预测顺铂介导的急性肾损伤的代谢组学:加拿大多中心成人和儿童研究
- 批准号:
402040 - 财政年份:2019
- 资助金额:
$ 51.01万 - 项目类别:
Operating Grants
Study of pathogenic mechanism of age-dependent chromosome translocation in adult acute lymphoblastic leukemia
成人急性淋巴细胞白血病年龄依赖性染色体易位发病机制研究
- 批准号:
18K16103 - 财政年份:2018
- 资助金额:
$ 51.01万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Causal effect of time-varying driving pressures on mortality in mechanically ventilated, adult patients with acute respiratory distress syndrome
时变驱动压力对机械通气成年急性呼吸窘迫综合征患者死亡率的因果影响
- 批准号:
377313 - 财政年份:2017
- 资助金额:
$ 51.01万 - 项目类别:
Studentship Programs
Role of SETBP1 in adult Ph+ acute lymphoblastic leukemia
SETBP1 在成人 Ph 急性淋巴细胞白血病中的作用
- 批准号:
9315111 - 财政年份:2016
- 资助金额:
$ 51.01万 - 项目类别:
Acute Inhibition of Adult-born Granule Cells and its Effect on Antidepressant Act
成体颗粒细胞的急性抑制及其抗抑郁作用
- 批准号:
8734273 - 财政年份:2013
- 资助金额:
$ 51.01万 - 项目类别: