NF-kappaB Cell Death Signaling

NF-kappaB 细胞死亡信号传导

基本信息

批准号：
8899973
负责人：
PATRICK J. DOLPH
金额：
$ 20.25万
依托单位：
DARTMOUTH COLLEGE
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：
2015-06-01 至 2017-05-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8899973
关键词：
Affect Alleles Alzheimer&apos s Disease Apoptotic Arrestins Binding Biological Models Caspase Cell Death Cell Death Signaling Process Cell Nucleus Cell Proliferation Cells Cessation of life Characteristics Collection Complex Cytoplasm Cytoprotection Degenerative Disorder Dorsal Drosophila genus Drosophila melanogaster Endocytosis Event Eye Future Genes Genetic Screening Gram-Negative Bacterial Infections Grant Health Homologous Gene Human Immune system Immunity Individual Inflammation Investigation Laboratories Light Mediating Membrane Methods Molecular Molecular Genetics Molecular Models Mutation NF-kappa B Natural Immunity Nerve Degeneration Neurologic Parkinson Disease Pathway interactions Patients Phenotype Photons Photoreceptors Prion Diseases Proteins RNA Interference Recruitment Activity Research Retina Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Rhodopsin Role Severities Signal Pathway Signal Transduction Symptoms Techniques Transcription Coactivator Vesicle Visual system structure Work fly genetic regulatory protein genome-wide human disease in vivo insight late endosome loss of function molecular modeling neuronal cell body novel protein aggregate protein misfolding public health relevance receptor receptor mediated endocytosis transcription factor

项目摘要

DESCRIPTION (provided by applicant): In the visual system, the activation of rhodopsin by a photon of light initiates a chain of events referred to as the photo transduction cascade. The inactivation of this cascade is achieved at one level by the binding of the regulatory protein arrestin to rhodopsin. A mechanism of photoreceptor cell degeneration has previously been described in Drosophila where the normally transient interaction between rhodopsin and arrestin is stabilized. These rhodopsin/arrestin complexes are internalized into the cell body of the photoreceptor cell resulting in the loss of nearly all rhodopsin from the rhabdomeric membrane. The rhodopsin is not degraded but instead accumulates in the late endosome as insoluble aggregates, eventually leading to photoreceptor cell death. Recently we have determined that the NF-kB homologues Relish Dorsal and two different innate immunity pathways are necessary for this form of photoreceptor cell degeneration. The innate immunity pathway is a highly conserved signaling pathway that protects cells from gram-negative bacterial infection. In addition to immunity signaling, NF-kB is a well-studied transcription factor that is also involved n cell proliferation, inflammation, and cell protection. Since NF-kB functions as an antiapoptotic molecule, the cell death inducing function found in the Drosophila retina is novel. In this grant, we propose to further investigate the role of NF-kB in endocytosis-mediated cell death. This will be accomplished by a genetic screen aimed at isolating suppressors of retinal degeneration. A subset of the suppressors will be selected for future study. This work is the first description of NF-kB signaling being utilized in retinal degeneration.

描述（由适用提供）：在视觉系统中，通过光的照片激活Rhodopsin，启动了一系列事件，称为Phototransduction Cascade。通过调节蛋白阻止蛋白与视紫红质的结合，在一个水平上实现了这种级联反应的失活。先前已经在果蝇中描述了感光细胞变性的机制，在果蝇中，杜鹃蛋白和抑制蛋白之间的正常瞬时相互作用稳定。这些视紫红质/阻滞蛋白复合物被内化到感光细胞的细胞体中，导致几乎所有的Rhodopsin因横纹膜损失而丧失。视紫红质不会降解，而是作为不溶性骨料积聚在晚期内体中，最终导致感光细胞死亡。最近，我们确定了NF-KB同源物津津有元，并且对于这种形式的感光细胞变性是必要的。先天免疫组织化学途径是一种高度保守的信号通路，可保护细胞免受革兰氏阴性细菌的感染。除了免疫信号传导外，NF-KB是一个良好的转录因子，也涉及N细胞增殖，炎症和细胞保护。由于NF-KB充当抗凋亡分子，因此在果蝇视网膜中发现的细胞死亡诱导功能是新颖的。在这笔赠款中，我们建议进一步研究NF-KB在内吞介导的细胞死亡中的作用。这将通过旨在隔离残余变性的补充的遗传筛查来实现。将选出补充剂的一个子集进行以后的研究。这项工作是在残留变性中使用的NF-KB信号传导的第一个描述。