Programmed Cell Death in Drosophila Development

果蝇发育中的程序性细胞死亡

基本信息

批准号：
8720780
负责人：
Kimberly A McCall
金额：
$ 36.18万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8720780
关键词：
Affect Animals Apoptosis Apoptotic Autophagocytosis Binding Biological Models Calcium Caspase Cell Death Cell Nucleus Cells Cellular biology Cessation of life Collaborations Confocal Microscopy DNA Development Developmental Cell Biology Disease Drosophila genus Epithelial Event Excision Family Gene Targeting Genes Genetic Goals Grant Homeostasis Human Inhibition of Apoptosis Investigation JNK-activating protein kinase MAPK8 gene Malignant Neoplasms Mammals Mitochondria Morphology Necrosis Neurodegenerative Disorders Nuclear Nurses Oocytes Oogenesis Ovary Pathway interactions Phenotype Play Process Proteins Regulation Research Role Signal Pathway Signal Transduction Snails Staging Stretching Time TimeLine Transcription Repressor/Corepressor egg fly genetic manipulation human disease insight killings mutant new therapeutic target novel public health relevance receptor reconstruction research study tool transcription factor transcription factor USF

项目摘要

DESCRIPTION (provided by applicant): Cell death is a fundamental process in animal development and homeostasis, and mis-regulation of cell death is associated with a large number of human diseases including cancer and neurodegenerative disorders. While much is known about mechanisms of apoptotic cell death, far less is known about non-apoptotic forms of cell death which contribute significantly to development and disease. Our research focuses on uncovering the mechanisms that control a non-apoptotic form of cell death that occurs naturally in the Drosophila ovary, a model system with powerful tools in genetics and cell biology. During late stages of oogenesis, germline- derived nurse cells undergo synchronous programmed cell death. In the prior grant periods, we determined that developmental nurse cell death can occur independently of apoptosis and autophagy genes, and nurse cell death displays hallmarks of necrosis. We recently discovered a transcription factor that inhibits nurse cell death more strongly that combined inhibition of apoptosis and autophagy. Furthermore, we have found that follicle cells, which surround the nurse cells, act non-cell-autonomously to promote nurse cell removal. We propose that nurse cell death involves collaboration between novel pathways acting autonomously in the germline and non-autonomously in the surrounding somatic follicle cells. This proposal aims to uncover the network acting in the nurse cells and follicle cells that culminates in nurse cell death. First, we will investigate the events occurring in follicle cells, nd how these coordinate with nurse cell death. Second, we will characterize the targets of transcription factors found to direct the cell- autonomous cell death pathway in nurse cells. Third, we will determine how the upstream activators of nurse cell death control specific nuclear events and interface with downstream effectors. Given the high degree of conservation of cell death mechanisms between Drosophila and mammals identified thus far, we expect that pathways that we uncover in the fly ovary will provide insight into the diversity of cell death mechanisms in humans. A complete understanding of the mechanisms controlling cell death may reveal new therapeutic targets for diseases with excessive or insufficient cell death such as neurodegenerative disorders and cancer.

描述（由申请人提供）：细胞死亡是动物发育和体内平衡的基本过程，细胞死亡的失调与包括癌症和神经退行性疾病在内的大量人类疾病有关。虽然人们对凋亡细胞死亡的机制了解很多，但对对发育和疾病有显着影响的非凋亡形式的细胞死亡却知之甚少。我们的研究重点是揭示控制果蝇卵巢中自然发生的非凋亡形式细胞死亡的机制，果蝇卵巢是一个在遗传学和细胞生物学方面具有强大工具的模型系统。在卵子发生的后期，生殖细胞衍生的滋养细胞经历同步的程序性细胞死亡。在之前的资助期间，我们确定发育性护士细胞死亡可以独立于细胞凋亡和自噬基因而发生，并且护士细胞死亡表现出坏死的特征。我们最近发现了一种转录因子，它可以结合细胞凋亡和自噬的抑制，更强烈地抑制护士细胞死亡。此外，我们发现围绕护理细胞的毛囊细胞非细胞自主地发挥作用以促进护理细胞的去除。我们认为，护士细胞死亡涉及种系中自主作用的新途径与周围体细胞滤泡细胞中非自主作用的新途径之间的协作。该提案旨在揭示在护士细胞和滤泡细胞中起作用并最终导致护士细胞死亡的网络。首先，我们将研究卵泡细胞中发生的事件，以及这些事件如何与护士细胞死亡相协调。其次，我们将描述在护士细胞中指导细胞自主细胞死亡途径的转录因子的靶标。第三，我们将确定护士细胞死亡的上游激活剂如何控制特定的核事件并与下游效应器相互作用。鉴于迄今为止发现的果蝇和哺乳动物之间细胞死亡机制的高度保守性，我们期望在果蝇卵巢中发现的途径将有助于深入了解人类细胞死亡机制的多样性。对控制细胞死亡的机制的全面了解可能会揭示细胞死亡过度或不足的疾病（例如神经退行性疾病和癌症）的新治疗靶点。