Transition zone control of ciliary signaling
Transition zone control of ciliary signaling
批准号:
10466835
负责人:
Jeremy F Reiter
金额:
$58.94万
依托单位国家:
美国
项目类别:
财政年份:
2011
资助国家:
美国
项目状态:
已结题
起止时间:
2011-07-18 至 2023-08-31
关键词:
AddressAdultAffectArchitectureBiochemicalBiologicalCell LineCell SurvivalCellsCiliaComplexCongenital AbnormalityCraniofacial AbnormalitiesCuesDataDefectDetectionDevelopmentEmbryoFaceGenesGeneticGoalsHereditary DiseaseHomeostasisHumanHuman bodyImageIn VitroInterphase CellInvestigationJoubert syndromeLinkLipidsMalignant NeoplasmsMediatingMembraneMicroscopyModelingMolecularMusMutant Strains MiceMutationNeural tubeOrganellesOrganismOrthologous GenePF4 GenePKD2 proteinPatternPhysiologicalPolycystic Kidney DiseasesPositioning AttributeProductionProsencephalonProteinsResolutionRestRoleSHH geneSignal TransductionSmell PerceptionStructureSurfaceTestingTissuesVisionWorkbaseciliopathycilium biogenesiscraniofacialcraniofacial developmentdevelopmental diseasedigitalexperimental studyhedgehog signal transductionhuman diseaseinsightintercellular communicationkinetosomemutantnovelprogenitorprotein complexsmoothened signaling pathwaytooltrafficking
中文摘要
项目摘要/摘要
人体内的许多细胞表面有一个称为初级纤毛的单一突起。
虽然初级纤毛的存在已经被承认了一个多世纪,但直到现在才变得清晰起来
最近,它们在检测和解释重要的细胞间线索方面发挥了作用。其中一些
信号,如刺猬信号,是胚胎模式和成年组织动态平衡的关键调节因素。
因此,Hedgehog信号的缺陷可能导致出生缺陷和某些形式的癌症。同样,
原发纤毛的缺陷会导致先天性纤毛疾病,如口腔面部指病和Joubert综合征,并可
这是更常见的人类疾病的基础,如多囊肾病。
为了在信号传递中发挥作用,初级纤毛需要保持与周围部分不同的组成
牢房。我们确定了睫状体底部的过渡区是睫状体的关键调节区域。
组成。为了了解过渡区如何控制纤毛上的蛋白质定位,我们将回答
三个互补的问题。
首先,由于过渡区是纤毛的一个复杂和高度结构化的区域,我们将
确定它是如何构建的。确定睫外蛋白复合体是如何产生过渡区的
解释影响非纤毛蛋白的突变是如何导致纤毛疾病的。
其次,我们将研究过渡区如何调节纤毛的蛋白质和脂肪定位。
了解不同的贩运机器及其货物如何使用不同的机制跨越
过渡区将有助于揭示这个门是如何控制纤毛蛋白质组成的。此外,我们将在
最近的数据表明,睫状膜的脂质成分是专门化的,对它的信号传递是必不可少的
通过检查纤毛脂如何进入纤毛并在那里被移行区丰富而发挥作用。这些
实验将演示蛋白质如何调节脂质成分以实现细胞器特有的功能。
第三,我们将确定过渡区如何调节颅面发育。许多纤毛病
与头面部缺陷有关,以及我们对面部移行区功能的研究
图案化揭示了纤毛信号调节哺乳动物发育的新方式。
通过阐明过渡区控制纤毛组成的机制,我们将有所帮助
阐明细胞如何将细胞器划分为执行多种信号功能
发育和生理功能。
英文摘要
Project summary/Abstract
Many cells in the human body possess a singular projection from their surface called a primary cilium.
Although the existence of primary cilia has been recognized for over a century, it has become clear only
recently that they function in the detection and interpretation of important intercellular cues. Some of these
cues, such as Hedgehog signals, are key regulators of embryonic patterning and adult tissue homeostasis.
Consequently, defects in Hedgehog signaling can cause birth defects and some forms of cancer. Similarly,
defects in primary cilia cause congenital ciliopathies such as Oro-facio-digital and Joubert syndromes, and can
underlie more common human diseases such as polycystic kidney disease.
To function in signaling, primary cilia need to maintain a different composition than surrounding parts of
the cell. We identified the transition zone, a region of the ciliary base, as a critical regulator of ciliary
composition. To understand how the transition zone controls which proteins localize to cilia, we will answer
three complementary questions.
First, given that the transition zone is a complex and highly structured region of the cilium, we will
determine how it is built. Identifying how extra-ciliary protein complexes generate the transition zone will
illuminate how mutations affecting non-ciliary proteins also cause ciliopathies.
Second, we will examine how the transition zone regulates protein and lipid localization to the cilium.
Understanding how different trafficking machines and their cargos use distinct mechanisms to cross the
transition zone will help reveal how this gate controls ciliary protein composition. Additionally, we will build on
recent data that the lipid composition of the ciliary membrane is specialized and essential for its signaling
functions by examining how ciliary lipids enter the cilium and enriched there by the transition zone. These
experiments will demonstrate how proteins regulate lipid composition to enable organelle-specific functions.
Third, we will determine how the transition zone regulates craniofacial development. Many ciliopathies
are associated with craniofacial defects, and our investigation of how transition zones function in facial
patterning is revealing novel ways in which ciliary signaling regulates mammalian development.
By elucidating the mechanisms by which the transition zone controls ciliary composition, we will help
illuminate how the cell compartmentalizes this organelle to perform diverse signaling functions critical for
development and physiological functioning.
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DOI:
10.1016/j.cell.2016.12.032
发表时间:
2017-01-12
期刊:
Cell
影响因子:
64.5
作者:
[Phua SC, Chiba S, Suzuki M, Su E, Roberson EC, Pusapati GV, Schurmans S, Setou M, Rohatgi R, Reiter JF, Ikegami K, Inoue T]
通讯作者:
Inoue T
DOI:
10.1016/j.devcel.2015.03.012
发表时间:
2015-03-23
期刊:
Developmental cell
影响因子:
11.8
作者:
[Yee LE, Reiter JF]
通讯作者:
Reiter JF
DOI:
10.1016/j.cub.2018.03.010
发表时间:
2018-04-23
期刊:
Current biology : CB
影响因子:
--
作者:
[Garcia G 3rd, Raleigh DR, Reiter JF]
通讯作者:
Reiter JF
DOI:
10.1016/j.devcel.2021.11.020
发表时间:
2021-12-20
期刊:
Developmental cell
影响因子:
11.8
作者:
[Xie C, Abrams SR, Herranz-Pérez V, García-Verdugo JM, Reiter JF]
通讯作者:
Reiter JF
DOI:
10.1126/science.1244689
发表时间:
2013-12-06
期刊:
Science (New York, N.Y.)
影响因子:
--
作者:
[de la Roche M, Ritter AT, Angus KL, Dinsmore C, Earnshaw CH, Reiter JF, Griffiths GM]
通讯作者:
Griffiths GM
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