Neuronal cell death in a genetic model

遗传模型中的神经细胞死亡

• 批准号: 7753663
• 负责人: NICHOLE L LINK
• 金额: $ 3.08万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-20 至 2011-02-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7753663
• 关键词: Address; Alleles; Alzheimer' s Disease; Animals; Apoptosis; Apoptotic; Caspase; Cell Death; Development; Disease; Dorsal; Drosophila genus; Genes; Genetic; Genetic Epistasis; Genetic Models; Human Pathology; Lead; Modeling; Molecular Machines; Mus; Mutation; Nervous system structure; Neurobiology; Neurons; Parkinson Disease; Pathology; Pathway interactions; Phenocopy; Phenotype; Protein Kinase; Regulation; Relative (related person); Role; Signal Transduction; Specific qualifier value; Work; apoptosis deregulation; fly; homeodomain; loss of function mutation; member; mutant; nervous system development; nervous system disorder; neuron development; neuron loss; novel; public health relevance

DESCRIPTION (provided by applicant): Deregulation of apoptosis can lead to neuronal loss and degeneration as seen in many neurological disorders such as Alzheimer's and Parkinson's disease. In order to effectively treat these diseases, it is important that we understand the mechanisms of cell death and how they contribute to human pathologies. Apoptosis functions through the apoptosome, a highly conserved molecular machine that controls caspase activation. The broad evolutionary conservation among metazoans permits us to take advantage of powerful genetic models to dissect the underlying function and regulation of the apoptosome. Because Drosophila is an exceptionally sophisticated model for both genetics and neurobiology, we can rigorously study the function of putative regulators of the apoptosome in neuronal development and neuronal pathologies. In flies, mutants of the apoptosome components, dark and drone, show distinct neuronal phenotypes that are manifestations of defective cell death. Using these phenotypes, we initiated a screen for conserved regulators and effectors of the apoptosome. The rationale for this initiative hinges on the unique phenotypes associated with loss-of-function mutations in dark and drone to identify putative regulators and effectors of the apoptosome. Over twenty cell death defective mutations that phenocopy dark and drone were recovered. Included among these is an allele of Homeodomain Interacting Protein Kinase (HIPK). Through unknown mechanisms, the mouse counterparts of this gene specify proper development of the nervous system and are implicated in the regulation of neuronal cell death. Through the use of novel null alleles at the HIPK locus, we have shown that HIPK is an important regulator of cell death in the developing animal and in the nervous system. My first aim will work to 1) determine where HIPK functions relative to known apoptotic players with epistasis studies, 2) further our understanding of the mechanism of HIPK action with respect to the apoptosome, and 3) place the action of HIPK in canonical signaling networks including Dorsal/NFKB. My second aim addresses an additional PCD defective mutation, pcdnI2, isolated from our screen but not yet implicated in cell death. By generating a novel null allele of pcdnI2, I will determine whether the implicated locus, CG31522, is responsible for cell death defective phenotypes, describe its role in developmental and neuronal cell death, and place its action relative to known members of the apoptotic pathway. PUBLIC HEALTH RELEVANCE: Apoptosis is a key component of many neurological disorders. Understanding apoptotic mechanisms will aid in treatment and understanding of these conditions.

描述（由申请人提供）：细胞凋亡的放松管制会导致神经元丧失和变性，如许多神经系统疾病，例如阿尔茨海默氏病和帕金森氏病。为了有效治疗这些疾病，重要的是要我们了解细胞死亡的机制及其对人类病理的贡献。细胞凋亡通过凋亡组的功能，这是一种控制caspase激活的高度保守的分子机。后生动物之间的广泛进化保护使我们能够利用强大的遗传模型来剖析凋亡小体的潜在功能和调节。由于果蝇是遗传学和神经生物学的一个异常复杂的模型，因此我们可以严格研究凋亡小体在神经元发育和神经元病理中的假定调节剂的功能。在苍蝇中，黑暗和无人机的凋亡组成分的突变体显示出独特的神经元表型，这些表型是缺陷细胞死亡的表现。使用这些表型，我们启动了一个保守的调节剂和凋亡组效应子的屏幕。该计划的基本原理取决于与黑暗和无人机中的功能丧失突变相关的独特表型，以识别凋亡组的推定调节剂和效应子。回收了二十多个细胞死亡缺陷突变，这些突变被发现了黑暗和无人机。其中包括同源域相互作用蛋白激酶（HIPK）的等位基因。通过未知的机制，该基因的小鼠对应物指定了神经系统的适当发展，并与神经元细胞死亡的调节有关。通过在HIPK基因座使用新的无效等位基因，我们表明HIPK是发育中动物和神经系统中细胞死亡的重要调节剂。我的第一个目标将对1）确定HIPK相对于具有上毒研究的已知凋亡参与者的功能，2）进一步了解我们对HIPK作用在凋亡组方面的机制的理解，以及3）将HIPK在包括背部/NFKB在内的规范信号网络中的作用。我的第二个目的解决了从屏幕上分离出来的额外的PCD有缺陷的突变PCDNI2，但尚未与细胞死亡有关。通过生成新的PCDNI2无效等位基因，我将确定所含义的基因座CG31522是否负责细胞死亡缺陷表型，描述其在发育和神经元细胞死亡中的作用，并将其相对于凋亡途径的已知成员发挥作用。公共卫生相关性：凋亡是许多神经系统疾病的关键组成部分。了解凋亡机制将有助于治疗和理解这些疾病。