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Developmental regulation by nuclear pore complex proteins

核孔复合蛋白的发育调节

基本信息

批准号：
9180714
负责人：
AMY M BEJSOVEC
金额：
$ 23.29万
依托单位：
DUKE UNIVERSITY
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：
2015-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9180714
关键词：
Adult Affect Aging Animals Architecture Binding Biochemical Biological Assay Biological Models Cell Nucleus Cell Survival Cell division Cell physiology Cells Cellular biology Childhood Chromatin Chromatin Structure Congenital Abnormality DNA Data Defect Development Developmental Process Disease Drosophila genus Embryo Enhancers Family Dasypodidae Fluorescent in Situ Hybridization Foundations Future Gene Expression Gene Targeting Genes Genetic Genetic Transcription Genome Global Change Goals Homologous Gene Human Human Development Hyperactive behavior Interphase Cell Investigation Leg Link Location Maintenance Malignant Neoplasms Microscopy Modeling Modification Molecular Molecular Genetics Muscular Dystrophies Nature Nuclear Nuclear Import Nuclear Lamina Nuclear Pore Nuclear Pore Complex Nuclear Pore Complex Proteins Nuclear Structure Nucleoplasm Outcome Pathology Pathway interactions Pattern Pattern Formation Play Pore Proteins Positioning Attribute Process Production Progeria Proteins RNA Interference Regulation Regulator Genes Research Role Salsola Signal Pathway Signal Transduction Source Structure Surveys System Techniques Testing Tissues Transcriptional Regulation Transposase WNT Signaling Pathway Wing Work beta catenin experimental study fly human disease imaginal disc in vivo inhibitor/antagonist insight knock-down loss of function mutant novel public health relevance response tool trafficking

项目摘要

DESCRIPTION (provided by applicant): A broad underlying cause of human disease is the incorrect spatial or temporal control of gene expression. The nuclear pore complex (NPC), which was long regarded simply as a gateway through which molecules move in and out of the nucleus, has emerged as an important modulator of expression. A novel link between the NPC and developmental signaling pathways, another key regulator of gene transcription, has been discovered in Drosophila, which motivates the proposed research. Megator, the fly homolog of the Tpr nuclear pore protein, was identified as a binding partner for the Wg/Wnt inhibitor, Tum. Loss of Megator function in the developing fly wing disrupted expression of Wg target genes without disrupting production of Wg itself, indicating that Megator is required for proper response to Wg/Wnt signaling. Two other nucleoporins (Nups) that were identified subsequently also appear to regulate developmental pathways. Loss of Nup154/155 or Nup214 function drastically disrupted the developing wing and leg without affecting other developing tissues. The unique pattern defects caused by Megator, Nup 154/155 or Nup214 disruption suggest that they are involved in cellular processes beyond just structural integrity of the NPC. They may target the nuclear import of key signaling pathway components, modulate signaling pathways independently of the NPC, or organize chromatin within the nucleus in ways that differentially influence the target genes of specific signaling pathways. The goal of this project is to distinguish among these hypotheses for the tissue-specific nature of the Nup activities, using the powerful molecular and genetic tools available in the Drosophila model system. Cell to cell signaling is required for embryonic patterning in all animals. In humans, loss of proper signaling leads to birth defects, whereas hyperactivity of some developmental pathways is associated with a variety of childhood and adult cancers. Because signaling pathways in Drosophila are highly conserved with humans, what is learned in the fly will be directly applicable to human cell biology. By studying these pathways and their interaction with the NPC, this project aims to provide new insight into disparate human disease states, and may reveal that they share similar cellular underpinnings. The results obtained in these exploratory experiments will guide future investigation into the relationship between signal transduction and the NPC. This work has the potential to blaze a new trail in understanding how nuclear architecture influences normal development and disease processes.