Regulation Of Tissue Growth And Morphogenesis By Fat Cadherins
脂肪钙粘蛋白对组织生长和形态发生的调节
基本信息
- 批准号:10470309
- 负责人:
- 金额:$ 39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAnimal ModelBiological ModelsCadherinsCell Adhesion MoleculesCell membraneCytoplasmic TailDefectDevelopmentDrosophila genusEndocytosisFatty acid glycerol estersGenesGrowthHennekam syndromeImageImage AnalysisMalignant NeoplasmsMediatingMorphogenesisMutationMyosin ATPaseOrganPathway interactionsPatternPlayRecyclingRegulationRoleShapesSignal PathwaySignal TransductionWorkbody systemdevelopmental diseaseinhibitorinsightmorphogensmutantnovelplanar cell polarityquantitative imagingtrafficking
项目摘要
Regulation of Tissue Growth and Morphogenesis by Fat Cadherins
Project Summary
Formation of optimally functioning organs of appropriate size and shape requires precise coordination of growth
and morphogenesis during development. The evolutionarily conserved cell adhesion molecules Dachsous and
Fat coordinately regulate tissue growth and patterning by influencing Hippo signaling and planar cell polarity
respectively. Mutations in these genes give rise to devastating Van Maldergem and Hennekam syndromes
characterized by congenital developmental defects of multiple organ systems. Further, mutations in these genes
are also implicated in several cancers. However, there are critical gaps in our understanding of how they regulate
growth and morphogenetic processes. We know little about how the spatial organization of the pathway is
established and maintained and how the Ds-Fat junctions get coordinately remodeled to allow morphogenesis.
Further, we lack a coherent view of how this pathway regulates Hippo signaling. Lastly, it is not clear how Fat
regulates organ shape. To address these critical gaps, we will use the fruit fly Drosophila, which provides a
robust model system to study this pathway. Our recent work has identified several novel regulators of this
pathway and uncovered some intriguing findings, which suggest that vesicular trafficking provides an important
layer of regulation in organization of the Fat signaling pathway, an aspect that has been overlooked so far. We
will investigate how an intricate interplay between the endocytic machinery and a competitive inhibitor plays a
critical role in organization of this pathway. Further, we will investigate how the Ds-Fat junctions get remodeled
by endocytosis in a mechanosensitive manner to allow morphogenesis. We have identified a key regulatory motif
in the Fat cytoplasmic domain and its interactors, which play an important role in Fat recycling to the plasma
membrane. We will characterize how this motif regulates Fat localization at the plasma membrane. Additionally,
we will investigate how Fat regulates Hippo signaling through the atypical myosin Dachs. Finally, we will examine
how Fat signaling affects the key morphogen gradients and conduct live imaging combined with quantitative
image analysis to identify the key cellular rearrangements that mediate organ shape alterations in Fat mutants.
These studies will provide novel mechanistic insight into Fat signaling pathway and address several longstanding
questions in the field and will help explain the developmental disorders resulting from dysregulation of this
pathway.
脂肪钙粘蛋白对组织生长和形态发生的调控
项目摘要
形成具有适当大小和形状的最佳功能器官需要精确的生长协调
以及发育过程中的形态发生。进化上保守的细胞粘附分子Dachsous和
脂肪通过影响Hippo信号传导和平面细胞极性来协调调节组织生长和图案化
分别这些基因的突变引起毁灭性的货车Maldergem和Hennekam综合征
以多器官系统的先天发育缺陷为特征。此外,这些基因的突变
也与几种癌症有关。然而,我们对它们如何监管的理解存在重大差距,
生长和形态发生过程。我们对这条路径的空间组织知之甚少
建立和维持以及DS-脂肪连接如何协调重塑以允许形态发生。
此外,我们缺乏关于该途径如何调节Hippo信号传导的一致观点。最后,不清楚脂肪如何
调节器官形状。为了解决这些关键的差距,我们将使用果蝇果蝇,它提供了一个
强大的模型系统来研究这一途径。我们最近的工作已经确定了几个新的监管机构,
途径,并揭示了一些有趣的发现,这表明囊泡运输提供了一个重要的,
脂肪信号通路组织中的调节层,这是迄今为止被忽视的一个方面。我们
将研究内吞机制和竞争性抑制剂之间复杂的相互作用如何发挥作用,
在这条道路的组织中发挥着重要作用。此外,我们将研究DS-脂肪连接是如何重塑的,
以机械敏感的方式通过内吞作用以允许形态发生。我们已经确定了一个关键的调控基序
在脂肪胞质结构域及其相互作用物中,其在脂肪向血浆的再循环中起重要作用
膜的我们将描述这个基序如何调节脂肪定位在质膜上。此外,本发明还
我们将研究脂肪如何通过非典型肌球蛋白Dachs调节Hippo信号。最后,我们将研究
脂肪信号传导如何影响关键形态梯度,并结合定量
图像分析,以确定关键的细胞重排,介导脂肪突变体的器官形状改变。
这些研究将为脂肪信号通路提供新的机制见解,并解决几个长期存在的问题。
在该领域的问题,并将有助于解释发育障碍所造成的失调,这
通路
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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Jyoti R. Misra其他文献
Effect of a single point mutation on the stability, residual structure and dynamics in the denatured state of GED: relevance to self-assembly.
单点突变对 GED 变性状态下的稳定性、残留结构和动力学的影响:与自组装的相关性。
- DOI:
- 发表时间:
2008 - 期刊:
- 影响因子:3.8
- 作者:
Jeetender Chugh;Shilpy Sharma;Dinesh Kumar;Jyoti R. Misra;R. Hosur - 通讯作者:
R. Hosur
1H, 15N, 13C resonance assignment of folded and 8 M urea-denatured state of SUMO from Drosophila melanogaster
果蝇 SUMO 折叠状态和 8 M 尿素变性状态的 1H、15N、13C 共振分配
- DOI:
10.1007/s12104-007-9072-6 - 发表时间:
2008 - 期刊:
- 影响因子:0.9
- 作者:
Dinesh Kumar;Ashutosh Kumar;Jyoti R. Misra;Jeetender Chugh;Shilpy Sharma;R. Hosur - 通讯作者:
R. Hosur
NMR‐derived solution structure of SUMO from Drosophila melanogaster (dSmt3)
NMR 衍生的果蝇 SUMO 溶液结构 (dSmt3)
- DOI:
- 发表时间:
2009 - 期刊:
- 影响因子:0
- 作者:
Dinesh Kumar;Jyoti R. Misra;Ashutosh Kumar;Jeetender Chugh;Shilpy Sharma;R. Hosur - 通讯作者:
R. Hosur
Jyoti R. Misra的其他文献
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{{ truncateString('Jyoti R. Misra', 18)}}的其他基金
Regulation Of Tissue Growth And Morphogenesis By Fat Cadherins
脂肪钙粘蛋白对组织生长和形态发生的调节
- 批准号:
10275573 - 财政年份:2021
- 资助金额:
$ 39万 - 项目类别:
Regulation of Organ Size and Shape by Fat Signaling
通过脂肪信号调节器官大小和形状
- 批准号:
10242136 - 财政年份:2019
- 资助金额:
$ 39万 - 项目类别:
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