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
• 负责人: Brian Anthony Pierchala
• 金额: $ 33.78万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10065062
• 关键词: p75; Ret; receptor; complex; integrator

 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.

 描述（由申请人提供）：在发育中的神经系统中，产生了多余的神经元，这些神经元是非必需的或连接不当的，并通过程序性细胞死亡消除。在外周神经元群体中，细胞凋亡的程度由神经支配靶点提供的促进存活的神经营养因子的有限供应和由成功竞争神经营养因子的神经元或“获胜神经元”分泌的细胞凋亡诱导竞争因子两者控制。“神经营养因子的流行家族之一是胶质细胞系源性神经营养因子（GDNF）家族配体（GFLs），其支持自主神经元、体感神经元和脊髓运动神经元的存活和轴突引导。最近，我们已经发现，GFL激活其共同的信号转导受体酪氨酸激酶，Ret，导致关联的Ret与p75，死亡受体的TNF家族的成员，在交感神经元和感觉神经元。重要的是，我们发现p75对体外GFL介导的Ret激活和感觉神经元存活至关重要。值得注意的是，我们还发现Ret与p75在BDNF刺激交感神经元后相互作用，这触发了这些神经元的凋亡性死亡。Ret基因缺失可抑制BDNF诱导的交感神经元凋亡。我们的总体假设是，p75-Ret受体复合物是一个开关调节生存和凋亡，这取决于配体促进组装的这种复杂的，并用于整合一致的生存和死亡信号。本申请的目的是双重的：（1）检验假设， p75对GFL介导的伤害感受神经元的存活至关重要;（2）验证Ret对交感神经元中死亡受体p75的凋亡功能是必需的假设。为了实现这些目标，我们将在原代神经元和转基因小鼠中使用生物化学和细胞生物学技术的组合。这些实验对于阐明神经营养因子和竞争因子的相反作用塑造外周感觉和自主神经回路的分子机制至关重要。此外，确定这些受体机制，创造生存和死亡之间的平衡，将使一个更合理的方法为神经系统损伤和疾病的治疗策略的发展。