Unexpected roles of phosphoinositides in the nucleus

磷酸肌醇在细胞核中的意外作用

基本信息

批准号：
10711033
负责人：
Suyong Choi
金额：
$ 35.67万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10711033
关键词：
1-Phosphatidylinositol 4-Kinase Autoimmunity Belief Biochemical Biological Cell Nucleus Cell physiology Cells Chromatin Complex Cytoskeleton DNA Double Strand Break DNA Repair Ensure Enzymes Epigenetic Process Functional disorder Gene Expression Generations Goals Health Human Knowledge Link Lipids Malignant Neoplasms Mediating Metabolic Diseases Microscopic Minor Molecular Nature Neurodegenerative Disorders Nuclear Pathogenesis Phosphatidylinositols Phospholipids Phosphotransferases Positioning Attribute Process Proteins Proteomics RNA Processing Regulation Repression Research Role Signal Pathway Signal Transduction Stimulus Transcription Coactivator Transcriptional Regulation cohort genetic corepressor genome-wide genome-wide analysis high resolution imaging human disease innovation insight novel novel strategies programs recruit spatiotemporal tool trafficking transcription factor

1-Phosphatidylinositol 4-Kinase Autoimmunity Belief Biochemical Biological Cell Nucleus Cell physiology Cells Chromatin Complex Cytoskeleton DNA Double Strand Break DNA Repair Ensure Enzymes Epigenetic Process Functional disorder Gene Expression Generations Goals Health Human Knowledge Link Lipids Malignant Neoplasms Mediating Metabolic Diseases Microscopic Minor Molecular Nature Neurodegenerative Disorders Nuclear Pathogenesis Phosphatidylinositols Phospholipids Phosphotransferases Positioning Attribute Process Proteins Proteomics RNA Processing Regulation Repression Research Role Signal Pathway Signal Transduction Stimulus Transcription Coactivator Transcriptional Regulation cohort genetic corepressor genome-wide genome-wide analysis high resolution imaging human disease innovation insight novel novel strategies programs recruit spatiotemporal tool trafficking transcription factor

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项目摘要

PROJECT SUMMARY / ABSTRACT Phosphoinositides (PIs) are a minor class of phospholipids often comprising less than 1% of the cellular lipid cohort. Despite the low abundance, PIs have huge impacts on cell physiology and alterations of PI signaling pathways are associated with the pathogenesis of many human diseases including neurodegenerative diseases, metabolic disorders, autoimmunity, and cancer. This pathophysiological importance is largely due to the signaling roles of PIs which depend on the subcellular distribution of PIs and on key interactions between PIs and PI effectors. A twist in PI signaling is that in contrast to general belief, a substantial fraction of PIs is found in non-membranous nuclear compartments. The nature and functions of nuclear PIs remains largely unknown due to the lack of systematic studies of nuclear PIs and PI effectors. We have expertise in defining and characterizing novel PI effector proteins involved in key signaling pathways including vesicular trafficking, cytoskeleton dynamics, and transcription regulation. Since PI kinases are often associated with PI effectors thus ensuring PI generation is spatiotemporally linked to PI effector activation, we have performed proteomic analyses to identify the interactomes of the nuclear PI-generating kinases. Out of these proteomic screens, we have validated several nuclear complexes that associate with nuclear PI kinases or with PIs themselves. The validated complexes include transcription factors and coactivators, epigenetic enzymes and associated corepressors, the DNA repair machinery, and factors involved in RNA processing. We recently discovered that nuclear PIs accumulate at distinct subnuclear regions such as nuclear speckles and DNA double-strand breaks. Based on our novel discoveries of PIs and PI kinases interacting with effectors in the nucleus, the overarching goal of my research program is to decipher the signaling pathways emanating from the nuclear PIs. Our overall hypothesis is that upon suitable stimuli the activation of nuclear PI kinase at specific subnuclear compartments elevates the local concentration of nuclear PIs and these nuclear PI foci function as platforms to regulate PI effectors recruited to the foci mediating transcription regulation and assembly of complexes that regulate epigenetic changes. The goals of my research programs for the next five years include dissecting the nature and subnuclear distribution of nuclear PIs using novel microscopic tools which will enable us to obtain high resolution images of the nuclear PIs, defining the new roles of PIs regulating chromatin positioning to nuclear speckles, and investigating novel roles of nuclear PIs in regulating gene expression with focuses on transcription regulation and epigenetic repression with innovative cell biological, genome-wide, and biochemical approaches. Upon the completion of the research programs, we will obtain insight into the unexpected roles and molecular mechanism of PIs in the nucleus, with the goal of identifying novel strategies for targeting the nuclear PI signaling pathways dysregulated in diverse human disease.

项目摘要 /摘要磷酸肌醇（PIS）是一类少数磷脂，通常不到细胞脂质的1％队列。尽管丰度较低，但PI对细胞生理和PI信号的改变有巨大影响途径与许多人类疾病的发病机理有关，包括神经退行性疾病，代谢疾病，自身免疫性和癌症。这种病理生理的重要性在很大程度上是由于 PI的信号传导作用，依赖于PI的亚细胞分布以及PI之间的关键相互作用和PI效应子。 PI信号的扭曲是，与一般信念相比，发现很大一部分PI 在非膜核室中。核PI的性质和功能在很大程度上仍然未知由于缺乏对核PI和PI效应子的系统研究。我们在定义和表征参与关键信号通路的新型PI效应蛋白，包括囊泡运输，细胞骨架动力学和转录调节。由于PI激酶通常与PI效应子相关确保PI生成与PI效应子激活有空间链接，我们进行了蛋白质组学分析确定核PI生成激酶的相互作用。在这些蛋白质组学屏幕中，我们有验证了几个与核PI激酶或PI本身相关的核复合物。已验证复合物包括转录因子和共激活剂，表观遗传酶和相关的核心， DNA修复机制以及RNA处理中涉及的因素。我们最近发现核pis 积聚在不同的亚核区域，例如核斑点和DNA双链断裂。基于我们对PI和PI激酶的新发现与核中效应子相互作用，这是总体目标我的研究计划是破译从核PI中发出的信号通路。我们的整体假设是，在适当的刺激下，核PI激酶在特定的亚核腔室中的激活提高核PI的局部浓度和这些核PI灶作为调节PI的平台的功能募集到调节调节复合物的转录调节和组装的焦点的效应子表观遗传变化。接下来五年我研究计划的目标包括剖析性质和使用新型的微观工具对核PI的亚核分布，这将使我们能够获得高分辨率核PI的图像，定义了调节染色质定位到核斑点的新作用的新作用，并研究核PI在调节基因表达中的新作用，重点是转录调节以及具有创新的细胞生物学，全基因组和生化方法的表观抑制作用。在完成研究计划的完成，我们将深入了解意外角色和分子机制核中的PI，目的是确定针对核PI信号通路的新型策略在多种人类疾病中失调。