A p75/Ret receptor complex as an integrator for survival and death
p75/Ret 受体复合物作为生存和死亡的整合器
基本信息
- 批准号:9269269
- 负责人:
- 金额:$ 33.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-05-15 至 2020-04-30
- 项目状态:已结题
- 来源:
- 关键词:Afferent NeuronsApoptosisApoptoticBiochemicalBiologicalBrain-Derived Neurotrophic FactorCell DeathCell LineCellsCessation of lifeClinical TrialsComplexDevelopmentDevelopmental ProcessDiseaseEquilibriumFamilyGDNF geneGrowth FactorImpairmentIn VitroInvestigationKnockout MiceKnowledgeLigandsMaintenanceMediatingMediator of activation proteinMethodsMolecularMotor NeuronsMusNerve Growth FactorsNervous System TraumaNervous system structureNeuronsNeurotrophic Tyrosine Kinase Receptor Type 1NociceptionNociceptorsOutcomeParkinson DiseasePathogenesisPeripheralPhenotypePhysiologicalPopulationSensorySignal TransductionSpinalStimulusStructure of superior cervical ganglionTNF geneTamoxifenTechniquesTestingTherapeuticTherapeutic AgentsTransgenic MiceTreatment ProtocolsUbiquitin Caxon guidancebaseexperimental studyglial cell-line derived neurotrophic factorin vivoinflammatory paininhibitor/antagonistmembernerve supplyneuron lossneurotrophic factorproto-oncogene protein c-retpublic health relevancereceptorrelease factorsmall molecule inhibitorsomatosensorytherapeutic developmenttraffickingtranscriptional coactivator p75
项目摘要
DESCRIPTION (provided by applicant): In the developing nervous system, excess neurons are generated which are nonessential, or inappropriately connected, and are eliminated by programmed cell death. In peripheral neuronal populations, the extent of apoptosis is governed by both a limited supply of survival-promoting neurotrophic factors supplied by targets of innervation and by apoptosis-inducing competition factors secreted by neurons that successfully compete for neurotrophic factors, or "winning neurons." One of the prevalent families of neurotrophic factors is the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), which support the survival and axon guidance of autonomic, somatosensory and spinal motor neurons. Recently we have discovered that GFL activation of their common signal transducing receptor tyrosine kinase, Ret, causes the association of Ret with p75, a member of the TNF family of death receptors, in sympathetic and sensory neurons. Importantly, we discovered that p75 was critical for GFL-mediated activation of Ret and survival of sensory neurons in vitro. Remarkably, we also found that Ret interacts with p75 upon BDNF stimulation of sympathetic neurons, which triggers the apoptotic death of these neurons. Ret deletion impaired BDNF-induced apoptosis of sympathetic neurons. Our overarching hypothesis is that the p75-Ret receptor complex is a switch regulating survival and apoptosis, depending upon which ligand promotes the assembly of this complex, and serves to integrate coincident survival and death signals. The objectives of this application are two-fold: (1) to test the hypothesis that
p75 is critical for the GFL-mediated survival of nociceptive neurons; (2) to test the hypothesis that Ret is necessary for the apoptotic function of the death receptor p75 in sympathetic neurons. In order to accomplish these objectives we will use a combination of biochemical and cell biological techniques in primary neurons and transgenic mice. These experiments are critical for delineating the molecular mechanisms by which the opposing actions of neurotrophic factors and competition factors sculpt peripheral sensory and autonomic circuits. Furthermore, the determination of these receptor mechanisms that create an equilibrium between survival and death will enable a more rational approach for the development of therapeutic strategies for nervous system injuries and diseases.
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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Brian Anthony Pierchala其他文献
Brian Anthony Pierchala的其他文献
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{{ truncateString('Brian Anthony Pierchala', 18)}}的其他基金
Growth factors in the development and physiology of geniculate taste neurons
膝状味觉神经元发育和生理学中的生长因子
- 批准号:
10659938 - 财政年份:2017
- 资助金额:
$ 33.78万 - 项目类别:
Growth factors in the development and physiology of geniculate taste neurons
膝状味觉神经元发育和生理学中的生长因子
- 批准号:
10101734 - 财政年份:2017
- 资助金额:
$ 33.78万 - 项目类别:
A p75/Ret receptor complex as an integrator for survival and death
p75/Ret 受体复合物作为生存和死亡的整合器
- 批准号:
10065062 - 财政年份:2015
- 资助金额:
$ 33.78万 - 项目类别:
A p75/Ret receptor complex as an integrator of survival and death
p75/Ret 受体复合物作为生存和死亡的整合者
- 批准号:
10093143 - 财政年份:2015
- 资助金额:
$ 33.78万 - 项目类别:
A p75/Ret Receptor Complex as an Integrator of Survival and Death
p75/Ret 受体复合体作为生存和死亡的整合者
- 批准号:
10612858 - 财政年份:2015
- 资助金额:
$ 33.78万 - 项目类别:
A p75/Ret Receptor Complex as an Integrator of Survival and Death
p75/Ret 受体复合体作为生存和死亡的整合者
- 批准号:
10399409 - 财政年份:2015
- 资助金额:
$ 33.78万 - 项目类别:
A p75/Ret receptor complex as an integrator for survival and death
p75/Ret 受体复合物作为生存和死亡的整合器
- 批准号:
9064238 - 财政年份:2015
- 资助金额:
$ 33.78万 - 项目类别:
A p75/Ret receptor complex as an integrator for survival and death
p75/Ret 受体复合物作为生存和死亡的整合器
- 批准号:
8960643 - 财政年份:2015
- 资助金额:
$ 33.78万 - 项目类别:
A p75/Ret receptor complex as an integrator of survival and death
p75/Ret 受体复合物作为生存和死亡的整合者
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