Regulation of Organ Size and Shape by Fat Signaling
通过脂肪信号调节器官大小和形状
基本信息
- 批准号:10242136
- 负责人:
- 金额:$ 24.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAwardBiological AssayBiological ModelsCell divisionCharacteristicsCouplesDefectDevelopmentDiseaseDominant-Negative MutationDrosophila genusDrosophila melanogasterDynaminEndocytosisEpithelialEventExhibitsFacultyFatty acid glycerol estersFoundationsGenesGenetic EpistasisGenetic ModelsGenetic ScreeningGenetic studyGoalsGrantGrowthHomologous GeneHumanImageInstitutionLeadLearningMapsMediatingMembraneMentorsMentorshipMolecularMorphogenesisMutationMyosin ATPaseOrganOrgan SizeOrganismPathogenesisPathway interactionsPhasePhenotypePlayPositioning AttributeProblem SolvingProcessRegulationResearchResearch PersonnelResourcesRoleSH3 DomainsShapesSignal PathwaySignal TransductionStructural Congenital AnomaliesStructureTemperatureTissuesTrainingTransferaseUbiquitinationUniversitiesWingWorkYeastsapical membranebasebody systemcongenital anomalydesignexperienceexperimental studygain of functiongirlsimprovedinnovationinsightinterestnoveloverexpressionpalmitoylationplanar cell polaritypreventprogramssuccesstraffickingubiquitin ligaseubiquitin-protein ligase
项目摘要
Project Summary/ Abstract
Coordination of growth and morphogenesis during development is critical for formation of organs of proper
shape and size and improperly sized and shaped organs often lead to organ malfunction and congenital
anomalies. The protocadherins, Dachsous (Ds) and Fat constitute a highly conserved signaling pathway that
regulates growth through its influence on Hippo signaling and morphogenesis by regulating planar cell polarity
and oriented cell divisions. Consistently, mutations affecting this pathway result in a number of diseases
affecting organ shape or size. Studies in Drosophila have provided important insights into the molecular
mechanisms that regulate organ size and shape by Fat signaling. Recently I have identified a new gene
Vamana, which is a critical downstream component of the Fat signaling pathway. Additionally, my recent work
has identified several novel regulators of this pathway and has led to intriguing findings that suggest that
vesicular trafficking plays a crucial role in regulating Fat signaling, an aspect that is very little explored. In Aim
1, I propose to investigate the vesicular trafficking mechanisms that organize this signaling pathway.
Specifically, I will study the interplay of ubiquitination and palmitoylation in trafficking of the components of this
pathway. From a pilot genetic screen, I have recently isolated a novel mutation, Big round wings (Brw), which
displays phenotypes characteristic of mutations in Fat-signaling pathway. In Aim 2, I will characterize how Brw,
regulates this pathway. Finally, based on the success of the pilot screen, I propose to identify additional
regulators of Fat signaling by an innovative forward gain of function screen. While my recent work has enabled
me to generate these intriguing findings and the research plan, my immediate goals are to obtain additional
training in live imaging, vesicular trafficking, ubiquitination and palmitoylation that are necessary to further
develop these projects. I have arranged a group of distinguished mentors, who will provide me with this
additional training. During the mentored phase of this award, I will train with Dr. Barth Grant to learn how to
approach and solve problems in vesicular trafficking. My mentor, Dr. Kenneth Irvine will provide training in live
imaging, and Dr. Marc Gartenberg will provide mentorship on development of the yeast based assay to identify
substrates of palmitoyl transferases. The proposed training combined with my previous research experience
will enable me to undertake a multipronged comprehensive approach to unravel novel molecular mechanisms
regulating Fat signaling. This research plan will also provide insight into pathogenesis of congenital
developmental defects arising from disruptions in Fat signaling. The pathway to independence award will
enable me to acquire the training and resources I need to achieve my immediate research goals. Further, the
proposed training and the innovative research program it supports will help me achieve my short-term goal of
obtaining a faculty position at a major university or research institution. The award will further assist me pursue
my long-term goal of understanding regulation of organ size and shape during development.
项目总结/摘要
在发育过程中,生长和形态发生的协调对于适当器官的形成至关重要。
形状和大小以及大小和形状不当的器官通常导致器官功能障碍和先天性
异常原钙粘蛋白、Dachsous(Ds)和Fat构成高度保守的信号通路,
通过影响Hippo信号传导和通过调节平面细胞极性的形态发生来调节生长
定向细胞分裂。因此,影响该途径的突变导致许多疾病
影响器官的形状或大小。对果蝇的研究提供了重要的见解,
通过脂肪信号调节器官大小和形状的机制。最近我发现了一个新的基因
Vamana,它是脂肪信号通路的关键下游成分。此外,我最近的工作
已经确定了这一途径的几种新的调节剂,并导致了有趣的发现,
囊泡运输在调节脂肪信号传导中起着至关重要的作用,这是一个很少探索的方面。在Aim中
1,我建议调查囊泡运输机制,组织这一信号通路。
具体地说,我将研究泛素化和棕榈酰化在运输这一组分中的相互作用。
通路从一个试点基因筛选,我最近分离出一种新的突变,大圆翼(Brw),
显示脂肪信号传导途径突变的表型特征。在目标2中,我将描述Brw,
调节这一途径。最后,在试点筛选成功的基础上,我建议确定额外的
Fat信号调节器通过功能屏幕的创新前向增益。虽然我最近的工作
为了产生这些有趣的发现和研究计划,我的直接目标是获得更多的
培训活成像,囊泡运输,泛素化和棕榈酰化,这是必要的,以进一步
发展这些项目。我已经安排了一批杰出的导师,他们将为我提供这一点,
额外的训练。在这个奖项的指导阶段,我将与巴斯格兰特博士一起培训,学习如何
探讨和解决囊泡运输中的问题。我的导师肯尼斯·欧文博士将提供现场培训
成像,和博士马克Gartenberg将提供指导,对发展酵母为基础的测定,以确定
棕榈酰转移酶的底物。建议的培训结合我以前的研究经验
将使我能够采取多管齐下的综合方法来解开新的分子机制,
调节脂肪信号传导。这项研究计划还将提供深入了解先天性
由于脂肪信号传导中断而引起的发育缺陷。独立之路奖将
使我能够获得我需要的培训和资源,以实现我的直接研究目标。此夕h
拟议的培训和创新的研究计划,它支持将帮助我实现我的短期目标,
在主要大学或研究机构获得教职。该奖项将进一步帮助我追求
我的长期目标是了解发育过程中器官大小和形状的调节。
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:
$ 24.4万 - 项目类别:
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:
10470309 - 财政年份:2021
- 资助金额:
$ 24.4万 - 项目类别:
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