Diversity Supplement -- Vertebrate Photoreceptor Development and Regeneration
Diversity Supplement -- Vertebrate Photoreceptor Development and Regeneration
批准号:
10650081
负责人:
Ann C Morris
金额:
$8.42万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
已结题
起止时间:
2012-08-01 至 2024-07-31
关键词:
AdoptionAnimal ModelBiochemicalBiologyBlindnessCell Differentiation processCell TransplantationCellsClustered Regularly Interspaced Short Palindromic RepeatsConeDataDefectDevelopmentDevelopmental BiologyDiseaseEmbryoEventEvolutionEye diseasesFamilyGene TargetingGeneticGenetic DiseasesGenetic TranscriptionGoalsHealthHomologous GeneHumanImageIn VitroInheritedInjuryLaboratoriesMediatingMicrophthalmosModelingMolecularMolecular GeneticsMolecular TargetMorphogenesisMorphologyMutationNatural regenerationNerve RegenerationNeuronsOpticsPathway interactionsPhotoreceptorsProtocols documentationRetinaRetinal ConeRetinal DegenerationRetinal DystrophyRetinitis PigmentosaRodRoleSOX11 geneSOX4 geneSignal PathwaySignal TransductionSuggestionSystemTherapeuticTimeTranscription RepressorTransgenic OrganismsTransplantationVascular Endothelial Growth FactorsVertebrate PhotoreceptorsVisualVisual impairmentVisual system structureWorkZebrafishbasecellular imagingclinical applicationdosageexperimental studygene regulatory networkgene therapygenetic approachgenome editingimaging modalityimprovedin vivoloss of functionmembermouse genomemutantneurogenesisnotch proteinnoveloptic cupparent grantphotoreceptor degenerationprecursor cellresponseretinal neuronretinal progenitor cellretinal rodsstem cell differentiationstem cell proliferationtherapy developmenttranscription factortransplantation therapy
中文摘要
项目摘要
遗传性视网膜营养不良,如视网膜色素变性(RP)是致盲的主要原因,
目前还无法治愈视网膜变性疾病的一种潜在治疗方法是细胞-
基于移植疗法,其中前体细胞被移植到患病的眼睛中,
取代失去的光感受器。虽然这是一个令人兴奋的可能性,
必须克服移植疗法的实施,包括
光感受器前体进入受体视网膜的困难,以及获得足够数量的光感受器前体的困难。
用于临床应用的感光体前体。为了改进体外培养这种细胞的方案,
细胞,我们必须有一个更好的理解转录网络,促进规范
感光细胞前体我们实验室的长期目标之一是为这些
研究斑马鱼感光细胞的发育和再生。斑马鱼是
特别是用于研究感光细胞生物学,因为它的视网膜含有大量的锥体
除了杆状病毒之外还有其他亚型。此外,斑马鱼视网膜能够再生神经元,
对实验性损伤的反应。本提案中所述的实验将确定以下方面的作用:
三种转录因子-- Sox、Sox 11和Her 9--在视网膜神经发生过程中通过
基因打靶和分子遗传学方法的应用。我们的具体目标如下:
具体目标I:确定Sox 4和Sox 11在感光细胞分化中的作用。使用新
产生功能丧失突变体,我们将1)确定Sox 4/11是否存在剂量效应
视杆细胞数量的活动; 2)使用最先进的延时成像来确定何时
并且其中需要Sox 4表达以实现适当的视杆细胞发育; 3)
精确地确定Sox 4/11如何调节Hh和Bmp信号传导;以及4)鉴定
Sox 4/11的目标。具体目标II:确定视网膜光感受器缺陷的原因和程度。
斑马鱼her 9突变体。在这个目标中,我们将1)确定感光细胞缺陷的机制,
her 9突变体; 2)确定Her 9的缺失是否损害视力; 3)鉴定上游信号传导
调节视网膜中her 9表达的途径;以及4)确定Her 9介导的视网膜中的HER 9表达是否与视网膜中的HER 9表达相关。
血管内皮生长因子在无血管斑马鱼视网膜中的表达调节视网膜祖细胞的增殖和
分化完成我们的提案将弥补我们对
脊椎动物感光细胞分化的分子机制,并揭示潜在的原则
本发明涉及用于治疗人视网膜变性疾病的方法的开发。
英文摘要
PROJECT SUMMARY
Inherited retinal dystrophies such as retinitis pigmentosa (RP) are a leading cause of blindness for
which there is currently no cure. One potential treatment for retinal degenerative diseases is cell-
based transplantation therapy, whereby precursor cells are transplanted into the diseased eye to
replace the lost photoreceptors. While this is an exciting possibility, several challenges to the
implementation of transplantation therapies must be overcome, including the inefficient integration of
photoreceptor precursors into the recipient retina, and the difficulty of obtaining sufficient numbers of
photoreceptor precursors for clinical application. To improve protocols for the in vitro culture of such
cells, we must have a better understanding of the transcriptional networks that promote specification
of photoreceptor precursors. One of the long-term goals of our laboratory is to contribute to these
efforts by studying photoreceptor development and regeneration in the zebrafish. The zebrafish is
especially useful for studying photoreceptor biology, because its retina contains numerous cone
subtypes in addition to rods. Furthermore, the zebrafish retina is able to regenerate neurons in
response to experimental damage. The experiments described in this proposal will define the role of
three transcription factors -- Sox, Sox11, and Her9 -- during retinal neurogenesis through the
application of gene targeting and molecular genetic approaches. Our specific aims are as follows:
Specific Aim I: Determine the role of Sox4 and Sox11 in photoreceptor differentiation. Using newly
generated loss-of-function mutants, we will 1) determine whether there is a dosage effect of Sox4/11
activity on rod photoreceptor number; 2) use state-of-the-art time-lapse imaging to determine when
and where Sox4 expression is required to achieve proper rod photoreceptor development; 3)
determine precisely how Sox4/11 regulate Hh and Bmp signaling; and 4) identify the molecular
targets of Sox4/11. Specific Aim II: Determine the cause and extent of photoreceptor defects in the
zebrafish her9 mutant. In this aim, we will 1) determine the mechanism for photoreceptor defects in
her9 mutants; 2) determine whether loss of Her9 impairs vision; 3) identify the upstream signaling
pathway(s) that regulate her9 expression in the retina; and 4) determine whether Her9-mediated
VEGF expression in the avascular zebrafish retina regulates retinal progenitor cell proliferation and
differentiation. Completion of our proposal will bridge important gaps in our understanding of the
molecular mechanisms of vertebrate photoreceptor differentiation, and reveal underlying principles
relevant to the development of approaches for the treatment of human retinal degenerative disease.
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DOI:
10.1371/journal.pgen.1004491
发表时间:
2014-07
期刊:
PLoS genetics
影响因子:
4.5
作者:
[Pillai-Kastoori L, Wen W, Wilson SG, Strachan E, Lo-Castro A, Fichera M, Musumeci SA, Lehmann OJ, Morris AC]
通讯作者:
Morris AC
DOI:
10.1002/dvdy.24235
发表时间:
2015-03
期刊:
Developmental dynamics : an official publication of the American Association of Anatomists
影响因子:
--
作者:
[Pillai-Kastoori L, Wen W, Morris AC]
通讯作者:
Morris AC
DOI:
10.1016/j.bbrc.2022.03.103
发表时间:
2022-06-11
期刊:
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
影响因子:
3.1
作者:
[Krueger, Laura A., Morris, Ann C.]
通讯作者:
Morris, Ann C.
DOI:
10.3389/fcell.2020.594290
发表时间:
2020
期刊:
Frontiers in cell and developmental biology
影响因子:
5.5
作者:
[Piedade WP, Titialii-Torres K, Morris AC, Famulski JK]
通讯作者:
Famulski JK
DOI:
10.3791/62296
发表时间:
2021-04-05
期刊:
Journal of visualized experiments : JoVE
影响因子:
--
作者:
[Petersen RA, Morris AC]
通讯作者:
Morris AC
共 6 条
Vertebrate photoreceptor development and regeneration
-
批准号:9751862
-
项目类别:
-
资助金额:$37.62万
-
财政年份:2012
-
负责人:Ann C Morris
-
依托单位:
Vertebrate photoreceptor development and regeneration
-
批准号:10459399
-
项目类别:
-
资助金额:$36.64万
-
财政年份:2012
-
负责人:Ann C Morris
-
依托单位:
Vertebrate photoreceptor development and regeneration
-
批准号:10227171
-
项目类别:
-
资助金额:$36.68万
-
财政年份:2012
-
负责人:Ann C Morris
-
依托单位:
The role of Insm1a in photoreceptor differentiation
-
批准号:8703706
-
项目类别:
-
资助金额:$29.01万
-
财政年份:2012
-
负责人:Ann C Morris
-
依托单位:
The role of Insm1a in photoreceptor differentiation
-
批准号:8372652
-
项目类别:
-
资助金额:$25.23万
-
财政年份:2012
-
负责人:Ann C Morris
-
依托单位:
The role of Insm1a in photoreceptor differentiation
-
批准号:8906868
-
项目类别:
-
资助金额:$24.58万
-
财政年份:2012
-
负责人:Ann C Morris
-
依托单位:
The role of Insm1a in photoreceptor differentiation
-
批准号:8511660
-
项目类别:
-
资助金额:$23.91万
-
财政年份:2012
-
负责人:Ann C Morris
-
依托单位:
The role of Insm1a in photoreceptor differentiation
-
批准号:9099846
-
项目类别:
-
资助金额:$25.02万
-
财政年份:2012
-
负责人:Ann C Morris
-
依托单位:
Vertebrate photoreceptor development and regeneration
-
批准号:9978812
-
项目类别:
-
资助金额:$37.85万
-
财政年份:2012
-
负责人:Ann C Morris
-
依托单位:
海外基金