Excitable Networks in Directed Cell Migration
定向细胞迁移中的兴奋网络
基本信息
- 批准号:10819960
- 负责人:
- 金额:$ 5万
- 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:2016-05-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAdultBackBiologicalBiological AssayCell Death InductionCell LineCellsChargeChemotactic FactorsCoupledCytoskeletonDictyosteliumDiseaseEmbryoEpithelial CellsFaceGrantHealthImageLipidsLocationMacrophageMalignant NeoplasmsMammalian CellMediatingMembraneMethodsModelingMolecularMonitorNormal CellOrganoidsPathologyPatternPhagosomesPhosphotransferasesPhysiologyProcessPropertyProtein GeranylgeranylationProteinsSeriesSignal TransductionStarvationSurfaceSystemVesiclecancer cellcell behaviorcell motilitycell transformationcomputer studiesdesigngenetically modified cellsinhibitormigrationneutrophilnovelnovel therapeutic interventionoptogeneticsresponsescreeningspatiotemporaltool
项目摘要
We are investigating molecular mechanisms of directed cell migration, a critical process in health and
disease, using Dictyostelium as a discovery tool to inform our studies of neutrophils, macrophages, and
epithelial cells. At the core of our working model are coupled Signal Transduction and Cytoskeletal
Excitable Networks, referred to as STEN and CEN which drive motility. The STEN integrates inputs from
directional sensing and polarity networks to bring about directed migration. In the last grant period, we
found that protrusions are governed by waves of coupled STEN-CEN activities and that manipulation of
negatively charged lipids on the inner face of the membrane can alter network excitability and control cell
behavior. The STEN-CEN concept is conserved in mammalian cells and the networks are hyperactivated
in transformed cells, augmenting motility and macropinocytosis. Since these processes require geranyl
geranylation, statins cause starvation of cancer cells. Finally, we found that vesicles internalized from
retracting protrusions carry “back” components to the rear of the cell contributing to polarity.
How do diverse cellular protrusions depend on the setpoint/threshold of STEN-CEN? We are
combining imaging, synthetic biological, and computational studies to prove that pseudopods,
lamellipods, forming phagosomes, and so on are closely related on a spectrum and interconvertible. We
will show that spatiotemporal patterns of activities and responses to acute molecular perturbations are
consistent across these protrusions and parallel those established in propagating STEN-CEN waves?
What explains the extraordinary coordination of activities in STEN and CEN? Surmising that charge on
the inner leaflet of the membrane is an organizer, we are 1) designing methods to directly monitor charge
in local regions; 2) determining how anionic lipids transiently decrease; 3) manipulating charge locally
with optogenetic systems; 4) examining how the location of key proteins is regulated by surface charge.
Is lowered STEN threshold a general property of transformed cells and can it be exploited? To address
this question, we are 1) comparing threshold indicators, such as propagating waves, with
macropinocytosis and statin sensitivity in a series of increasingly metastatic cell lines and organoids; 2)
identifying the essential geranylgeranylated proteins in STEN; 3) genetically engineering cells to increase
threshold to normalize cancer cells or further decrease threshold to induce cell death.
How does control of STEN and CEN at the cell poles mediate directional sensing and polarity? First,
using a novel suppression assay, we are screening kinase and substrate deficient cells to identify global
inhibitors. Second, we are studying membrane flow in a variety conditions to pursue our “reverse
fountain” model and reconcile with alternate models that argue membrane flows from front to back.
1
我们正在研究定向细胞迁移的分子机制,这是健康和
疾病,使用Dictyosteopathy作为发现工具,为我们的中性粒细胞,巨噬细胞和
上皮细胞我们工作模型的核心是耦合的信号转导和细胞骨架
兴奋性网络,称为STEN和CEN,驱动运动。STEN集成了来自
定向传感和极性网络,以实现定向迁移。在过去的一段时间里,我们
发现突起是由耦合STEN-CEN活动的波控制的,
膜内表面上的带负电荷的脂质可以改变网络的兴奋性并控制细胞
行为STEN-CEN概念在哺乳动物细胞中是保守的,并且网络被过度激活
在转化细胞中,增强运动性和巨胞饮作用。由于这些过程需要香叶基
香叶基化,他汀类药物引起癌细胞饥饿。最后,我们发现小泡从
缩回的突起将有助于极性的组分“带回”到电池的后部。
不同的细胞突起如何取决于STEN-CEN的设定点/阈值?我们
结合成像,合成生物学和计算研究,证明伪足,
板状体、形成吞噬体等在光谱上密切相关且相互转化。我们
将显示活动的时空模式和对急性分子扰动的反应,
在这些突起和平行的传播STEN-CEN波建立一致?
如何解释STEN和CEN活动的非凡协调?推测一下
膜的内部小叶是组织者,我们1)设计直接监测电荷的方法
在局部区域; 2)确定阴离子脂质如何瞬时减少; 3)局部操纵电荷
与光遗传学系统; 4)研究关键蛋白质的位置是如何由表面电荷调节的。
降低的STEN阈值是转化细胞的一般特性吗?它可以被利用吗?解决
这个问题,我们是1)比较阈值指标,如传播波,与
在一系列转移性增加的细胞系和类器官中的巨胞饮和他汀敏感性; 2)
鉴定STEN中必需的香叶基香叶基化蛋白; 3)基因工程细胞以增加
降低阈值以使癌细胞正常化或进一步降低阈值以诱导细胞死亡。
细胞两极的STEN和CEN是如何控制方向感和极性的?第一、
使用一种新的抑制试验,我们正在筛选激酶和底物缺陷的细胞,以确定全球
抑制剂的第二,我们研究了各种条件下的膜流动,以追求我们的“逆
喷泉”模型,并调和与替代模型,认为膜流从前面到后面。
1
项目成果
期刊论文数量(29)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Excitable Signal Transduction Networks in Directed Cell Migration.
- DOI:10.1146/annurev-cellbio-100616-060739
- 发表时间:2017-10-06
- 期刊:
- 影响因子:11.3
- 作者:Devreotes PN;Bhattacharya S;Edwards M;Iglesias PA;Lampert T;Miao Y
- 通讯作者:Miao Y
Correction for Edwards et al., Insight from the maximal activation of the signal transduction excitable network in Dictyostelium discoideum.
对 Edwards 等人的更正,从盘基网柄菌中信号转导可兴奋网络的最大激活的见解。
- DOI:10.1073/pnas.1809928115
- 发表时间:2018
- 期刊:
- 影响因子:11.1
- 作者:
- 通讯作者:
Coordination of Receptor Tyrosine Kinase Signaling and Interfacial Tension Dynamics Drives Radial Intercalation and Tube Elongation.
- DOI:10.1016/j.devcel.2018.03.011
- 发表时间:2018-04-09
- 期刊:
- 影响因子:11.8
- 作者:Neumann NM;Perrone MC;Veldhuis JH;Huebner RJ;Zhan H;Devreotes PN;Brodland GW;Ewald AJ
- 通讯作者:Ewald AJ
Actuation of single downstream nodes in growth factor network steers immune cell migration.
生长因子网络中单个下游节点的激活可引导免疫细胞迁移。
- DOI:10.1016/j.devcel.2023.04.019
- 发表时间:2023
- 期刊:
- 影响因子:11.8
- 作者:Pal,DhimanSankar;Banerjee,Tatsat;Lin,Yiyan;deTrogoff,Félix;Borleis,Jane;Iglesias,PabloA;Devreotes,PeterN
- 通讯作者:Devreotes,PeterN
The effects of statins in patients with advanced-stage cancers - a systematic review and meta-analysis.
- DOI:10.3389/fonc.2023.1234713
- 发表时间:2023
- 期刊:
- 影响因子:4.7
- 作者:
- 通讯作者:
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Peter N Devreotes其他文献
Peter N Devreotes的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Peter N Devreotes', 18)}}的其他基金
ZEISS AXIOVERT 200-M FOR TIME-LAPSE MICROSCOPY: CANCER
用于延时显微镜的蔡司 AXIOVERT 200-M:癌症
- 批准号:
7166650 - 财政年份:2005
- 资助金额:
$ 5万 - 项目类别:
ZEISS AXIOVERT 200-M FOR TIME-LAPSE MICROSCOPY: KIDNEY
用于延时显微镜的蔡司 AXIOVERT 200-M:肾脏
- 批准号:
7166649 - 财政年份:2005
- 资助金额:
$ 5万 - 项目类别:
ZEISS AXIOVERT 200-M FOR TIME-LAPSE MICROSCOPY: CELL BIOLOGY
用于延时显微镜的蔡司 AXIOVERT 200-M:细胞生物学
- 批准号:
7166651 - 财政年份:2005
- 资助金额:
$ 5万 - 项目类别:
2005 Gradient Sensing and Directed Cell Migration GRC
2005年梯度传感和定向细胞迁移GRC
- 批准号:
6941039 - 财政年份:2005
- 资助金额:
$ 5万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 5万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 5万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 5万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 5万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 5万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 5万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 5万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 5万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 5万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 5万 - 项目类别:
Research Grant