Perturbations of host cell signaling by a complex hepatotropic pathogen
Perturbations of host cell signaling by a complex hepatotropic pathogen
批准号:
9896827
负责人:
Alexis Kaushansky
金额:
$41.16万
依托单位国家:
美国
项目类别:
财政年份:
2013
资助国家:
美国
项目状态:
已结题
起止时间:
2013-04-01 至 2022-03-31
关键词:
AntimalarialsApoptosisBindingBiteCell Cycle ArrestCell DeathCellsCessation of lifeComplexCulicidaeDataDevelopmentEnvironmentEphA2 ReceptorEquilibriumErythrocytesFirst Independent Research Support and Transition AwardsFosteringGrantGrowth and Development functionHepatocyteHeterogeneityHost DefenseHost Defense MechanismHumanInfectionIntegration Host FactorsInternetInvestigationIronLeadLife StyleLigandsLiverMalariaMalignant - descriptorMediatingMedicalMolecularMonitorMusNatureParasitesParasitic infectionPathway interactionsPlasmodiumPlasmodium falciparumPlayProphylactic treatmentProtein p53ProteinsResistance developmentResourcesRodentRoleSignal PathwaySignal TransductionSporozoitesTP53 geneTestingTherapeuticbasecombatexperimental studyinhibitor/antagonistinsightmalaria infectionnovelpathogenpreventreceptorresponsesmall moleculesuccesstooltransmission process
中文摘要
病原体必须成功地在宿主复杂的相互作用网络中生存。在
英文摘要
Pathogens must successfully navigate the complex interaction networks of their hosts to survive. During
malaria parasite liver stage infection, parasites protect their host hepatocyte by preventing its death and
exploiting the host cell resources for growth and development. The host hepatocyte molecular signaling
landscape that facilitates successful liver stage replication has not been elucidated, yet it is highly medically
relevant. During the first award period of this grant, we have made significant strides towards elucidating a
number of signaling pathways upon which the malaria parasite relies and also identified the critical host
receptor which parasites engage during entry to establish a permissive environment for intracellular replication
and optimal development. We have generated preliminary data that suggests that malaria parasites must not
only control conventional forms of host cell defense such as apoptosis, but also must carefully regulate an iron-
dependent form of cell death called ferroptosis, which to our knowledge has never before been implicated in
host defense against pathogen. This proposal aims to fully delineate the pro-death milieu that the parasite can
evade, and what perturbations lead to the demise of the wild-type parasite. We will test the hypothesis that the
tumor suppressor P53 is the regulator of ferroptosis in infected cells. We will build on our data which
demonstrates that P53 is suppressed by Plasmodium infection, and increasing P53 levels can eliminate liver
stage parasites. Finally, we will build on our recent discovery that parasites select a subset of hepatocytes for
infection and determine the impact of this selection on establishing optimal host conditions for parasite survival.
Throughout the proposed experiments, we will monitor hepatocyte signals not only in response to rodent
malaria infection, but also in response to the most deadly human malaria parasite, Plasmodium falciparum, in
part by using hepatocytes from a mouse with a humanized liver. The proposed studies will lead to a more
comprehensive understanding of the hepatocyte signaling landscape that regulates the success or demise of
the Plasmodium liver stage. Accomplishing our aims opens the possibility of altering key host factors with
small-molecules that could prevent a wild-type parasite from progressing to symptomatic erythrocyte infection.
Such a host-based approach for prophylaxis is novel and will circumvent the massive problem of continuously
developing resistance to standard antimalarial drugs. This approach is further fostered by the fact that many
hepatocyte proteins are already targets of known therapeutic inhibitors. A more detailed understanding of the
complex perturbations elicited by this important intracellular pathogen might also reveal new aspects of
hepatocyte signaling.
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Elucidating host phosphosignaling regulation of Plasmodium vivax liver stage
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批准号:10056490
-
项目类别:
-
资助金额:$28.18万
-
财政年份:2020
-
负责人:Alexis Kaushansky
-
依托单位:
Elucidating host phosphosignaling regulation of Plasmodium vivax liver stage
-
批准号:10170244
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项目类别:
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资助金额:$21.38万
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财政年份:2020
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负责人:Alexis Kaushansky
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依托单位:
Investigating hepatocyte signaling driven by host-pathogen interactions
-
批准号:8821942
-
项目类别:
-
资助金额:$12.91万
-
财政年份:2015
-
负责人:Alexis Kaushansky
-
依托单位:
Investigating hepatocyte signaling driven by host-pathogen interactions
-
批准号:9203313
-
项目类别:
-
资助金额:$24.9万
-
财政年份:2015
-
负责人:Alexis Kaushansky
-
依托单位:
Perturbations of host cell signaling by a complex hepatotropic pathogen
-
批准号:10677933
-
项目类别:
-
资助金额:$63.0万
-
财政年份:2013
-
负责人:Alexis Kaushansky
-
依托单位:
Investigating the Role of Cellular Signaling in Liver-Stage Malaria Infection
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批准号:8001602
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项目类别:
-
资助金额:$4.96万
-
财政年份:2010
-
负责人:Alexis Kaushansky
-
依托单位:
Investigating the Role of Cellular Signaling in Liver-Stage Malaria Infection
-
批准号:8282905
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项目类别:
-
资助金额:$5.42万
-
财政年份:2010
-
负责人:Alexis Kaushansky
-
依托单位:
Investigating the Role of Cellular Signaling in Liver-Stage Malaria Infection
-
批准号:8090318
-
项目类别:
-
资助金额:$5.24万
-
财政年份:2010
-
负责人:Alexis Kaushansky
-
依托单位:
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