Neuronal Cell Death Regulation in Drosophila

果蝇神经细胞死亡调节

• 批准号: 7049790
• 负责人: FLORENCE M DAVIDSON
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7049790
• 关键词: Drosophilidae; G protein; Picornaviridae; arthropod genetics; biological models; biological signal transduction; cell death; cell surface receptors; disease /disorder onset; gene expression; gene mutation; genetic screening; neurogenetics; neurons; neuroregulation; retina degeneration; rhodopsin; virus diseases; visual photoreceptor

Our aim is to understand the control of neuronal cell death. We study this in terminally differentiated photoreceptor neurons (PRNs) of the retina. Our studies utilize Drosophila, where PRNs degenerate and die in response to some of the same stimuli that cause blindness in humans. We expect these studies to yield insight into mechanisms and possible therapies for a variety of chronic diseases, including cancer and degenerative CNS disorders.Our studies have elucidated environmental, genetic, and epigenetic factors controlling PRN degeneration and death. These include light, cell-death-regulatory genes such as hid, TRAF, caspases and dIAP1, and the ras mitogen-activated kinase pathway genes. Where investigated, we found that suppression of degeneration resulted in preservation of visual function, underscoring our earlier finding that degeneration is the cause, rather than consequence, of loss of PRN function. By genetic screening, we have identified additional suppressor and enhancer loci; a current aim is to pinpoint the genes responsible. A related aim is to incorporate genomics to accelerate the pace of gene discovery. Pilot experiments indicate the feasibility of this approach. In addition, we have discovered an apparent correlation between picornaviral infection and the age of onset of PRN degeneration. This suggests a potentially significant factor in the well-known variability of neurodegenerative phenotypes in different individuals. Experiments are underway to confirm the identity of this putative viral trigger.Additional areas of research include ultrastructural analyses of the connection between PRN degeneration and death, studies of the role of native rhodopsin in cell viability, and generation of transgenic constructs for probing the biochemistry of degeneration. Highlights include the finding that rhodopsin mutations causing degeneration in humans and flies are partial-loss-of-function mutations, rather than toxic-gain-of-function as previously believed. This reframes the mechanistic questions from "How do misfolded rhodopsins kill cells?" to "How does wild type rhodopsin keep cells alive?" Given the membership of rhodopsin in the GPCR family of proteins, these results are consistent with emerging evidence of a regulatory role for GPCRs in normal cell death regulation. Elucidating the molecular links between native rhodopsin function and PRN integrity/viability will thus be a major future focus.

我们的目标是了解神经元细胞死亡的控制。我们在视网膜终末分化的感光神经元（PRN）中研究这一点。我们的研究利用果蝇，其中 PRN 会因某些导致人类失明的相同刺激而退化并死亡。我们期望这些研究能够深入了解各种慢性疾病的机制和可能的治疗方法，包括癌症和退行性中枢神经系统疾病。我们的研究阐明了控制 PRN 变性和死亡的环境、遗传和表观遗传因素。这些包括光、细胞死亡调节基因，如 hid、TRAF、caspases 和 dIAP1，以及 ras 丝裂原激活激酶途径基因。在研究中，我们发现抑制变性会导致视觉功能的保留，这强调了我们之前的发现，即变性是 PRN 功能丧失的原因，而不是结果。通过基因筛选，我们已经确定了额外的抑制子和增强子位点；当前的目标是查明相关基因。一个相关的目标是整合基因组学来加快基因发现的步伐。中试实验表明了该方法的可行性。此外，我们发现小核糖核酸病毒感染与 PRN 变性的发病年龄之间存在明显的相关性。这表明不同个体神经退行性表型的众所周知的变异性存在潜在的重要因素。实验正在进行中，以确认这种假定的病毒触发因素的身份。其他研究领域包括 PRN 变性和死亡之间联系的超微结构分析、天然视紫红质在细胞活力中的作用的研究，以及用于探测 PRN 生物化学的转基因构建体的生成退化。亮点包括发现导致人类和果蝇退化的视紫红质突变是部分功能丧失突变，而不是之前认为的毒性功能获得突变。这重新构建了“错误折叠的视紫红质如何杀死细胞？”的机制问题。到“野生型视紫红质如何保持细胞存活？”鉴于视紫红质属于 GPCR 蛋白家族，这些结果与 GPCR 在正常细胞死亡调节中发挥调节作用的新证据一致。因此，阐明天然视紫红质功能和 PRN 完整性/活力之间的分子联系将是未来的主要焦点。