Collaboration between Phosphatidylserine receptors
磷脂酰丝氨酸受体之间的协作
基本信息
- 批准号:9192004
- 负责人:
- 金额:$ 5.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-12-01 至 2019-11-30
- 项目状态:已结题
- 来源:
- 关键词:ActinsApoptosisApoptoticAppearanceBindingCRISPR/Cas technologyCaenorhabditis elegansCell NucleusCell Surface ReceptorsCell membraneCell surfaceCellsCessation of lifeChronicChronic Obstructive AsthmaCollaborationsDataDefectDevelopmentDiseaseDissectionDrosophila genusEatingExcisionF-ActinGenesGlassHomeostasisHumanImmuneImmune responseIndividualInfectionInflammationLightLungMediatingMembraneMicroscopeMicrospheresMolecularMusNuclearPathogenesisPathway interactionsPhagocytesPhosphatidylserinesPlayProcessRadiationReceptor SignalingRecruitment ActivityReportingRoleSignal TransductionSurfaceSystemTestingTherapeuticTissuesTotal Internal Reflection FluorescentTranslatingZebrafishabstractingcancer therapycell injurychemotherapyin vitro Modelin vivoin vivo imaginginsightoptogeneticsphosphatidylserine receptorpreventprogramsreceptorreceptor functionreconstitutiontherapy development
项目摘要
Abstract
Apoptosis, or programed cell death, is a common occurrence during development, pathogenesis and tissue
homeostasis. The efficient removal of apoptotic cell corpses is crucial for preventing inflammation and a
potentially damaging immune response. For this reason, enhancing apoptotic corpse clearance may be an
effective strategy to resolve damaging inflammation following infection or aggressive cancer therapies that
overwhelm the endogenous system for removing apoptotic cells. Developing these therapies requires a deeper
understanding for how apoptotic corpse clearance pathways are activated. Dying cells recruit phagocytes
through `eat me' signals, the most widespread of which is phosphatidylserine (PS). Several PS-recognizing
receptors have been implicated in apoptotic corpse clearance but many aspects of their function are still
unclear: does each receptor regulate distinct aspects of the corpse clearance pathway or do they additively
converge on the same downstream targets? How are the PS receptors activated and how is this activation
translated into F-actin reorganization and engulfment? In particular, the phosphatidylserine receptor (PSR)
plays a highly conserved role in promoting clearance of apoptotic corpses, but the mechanism by which PSR
promotes corpse clearance is not known. I will examine the collaboration between two conserved PS-
recognizing receptors, the PS receptor (PSR) and CED-1/Draper, using a combination of in vivo imaging in C.
elegans and reconstituting engulfment pathways in Drosophila S2 cells. In the C. elegans germline, I will use a
dual inverted selective plane microscope (diSPIM) to examine phagocytic cup formation, F-actin dynamics and
efficiency of corpse clearance. This will determine which steps in the apoptotic corpse clearance program are
regulated by PSR-1, CED-1 or both receptors. To rapidly dissect the mechanism for PSR function, I will
reconstitute the apoptotic corpse clearance pathway in Drosophila S2 cells. My preliminary data shows that
ectopically expressing dPSR transforms S2 cells from poor phagocytes into efficient engulfers of PS-coated
glass microspheres. I will determine if PSR partitions with Draper or F-actin into microdomains of active
signaling in the plasma membrane, whether nuclear or only membrane-bound PSR signaling is required to
promote engulfment, and if PSR is activated by oligomerization. Together, these studies will give insight into
the function of PSR, a highly conserved yet poorly understood PS receptor, and elucidate how multiple PS
receptors collaborate to promote clearance of apoptotic cell corpses.
摘要
细胞凋亡或程序性细胞死亡是发育、发病和组织过程中常见的现象
体内平衡。有效清除凋亡细胞尸体对于预防炎症和炎症反应至关重要。
可能破坏免疫反应由于这个原因,增强凋亡尸体清除可能是一种有效的方法。
有效的策略来解决感染或侵袭性癌症治疗后的破坏性炎症,
压倒了去除凋亡细胞的内源性系统。开发这些疗法需要更深入的
了解凋亡尸体清除途径是如何被激活的。垂死的细胞募集吞噬细胞
通过“吃我”信号,其中最普遍的是磷脂酰丝氨酸(PS)。几种PS识别
受体与凋亡尸体清除有关,但其功能的许多方面仍不清楚。
不清楚:每种受体是否调节尸体清除途径的不同方面,或者它们是相加的
收敛于相同的下游目标?PS受体是如何被激活的
转化为F-肌动蛋白重组和吞噬特别是磷脂酰丝氨酸受体(PSR)
在促进凋亡尸体的清除中起着高度保守的作用,但PSR的机制
尸体清理的速度还不清楚我将研究两个保守的PS之间的合作-
识别受体,PS受体(PSR)和CED-1/德雷珀,使用在C.
elegans和重建吞噬途径在果蝇S2细胞。在C.我会用一个
双倒置选择性平面显微镜(diSPIM)检查吞噬杯形成,F-肌动蛋白动力学和
尸体清理效率。这将决定哪些步骤在凋亡尸体清除程序是
受PSR-1、CED-1或这两种受体调节。为了快速剖析PSR功能的机制,我将
在果蝇S2细胞中重建凋亡尸体清除途径。我的初步数据显示
异位表达dPSR使S2细胞从弱吞噬细胞转变为PS包被的有效吞噬细胞。
玻璃微球我将确定PSR是否与德雷珀或F-肌动蛋白分区成活性微区。
信号在质膜,无论是核或只有膜结合的PSR信号是必需的,
促进吞噬,并且如果PSR被寡聚化激活。总之,这些研究将深入了解
PSR是一种高度保守但知之甚少的PS受体,
受体协同促进凋亡细胞尸体的清除。
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(1)
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Meghan A Morrissey其他文献
Meghan A Morrissey的其他文献
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{{ truncateString('Meghan A Morrissey', 18)}}的其他基金
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