The Biology of Inositol Polyphosphate Signaling

肌醇多磷酸信号传导的生物学

基本信息

批准号：
8517309
负责人：
John D. York
金额：
$ 39万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-05-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8517309
关键词：
Apoptosis Basic Science Binding Biology Cell Count Cell Death Cell physiology Cells Cellular Morphology Cellular biology Chemicals Code Complex Cyclins Defect Development Diphosphates Drosophila melanogaster Enzymes Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Grant Growth Health Histone Deacetylase Human Inositol Inositol Metabolism Pathway Inositol Phosphates Knowledge Lead Lipids Mediating Metabolism Modeling Molecular Nuclear Nucleotides Nutrient Organism Output Pathway interactions Pattern Phosphoric Monoester Hydrolases Phosphotransferases Polyphosphate kinase Polyphosphates Public Health Regulation Research Response Elements Role Signal Pathway Signal Transduction Signal Transduction Pathway Specificity Structure Structure-Activity Relationship Telomere Maintenance Translating Work base cell growth design genetic analysis human disease imaginal disc improved induced pluripotent stem cell inorganic phosphate insight mRNA Export novel public health relevance receptor response sensor synthetic biology transcription factor

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this grant is the elucidation of inositol polyphosphate (IP) signaling pathways and determination of the mechanisms by which cells use them to elicit selective intracellular responses. We have taken a molecular approach to understanding these pathways, and have collectively cloned and identified the function of numerous enzymes involved in the metabolism of IP messengers. This proposal focuses on the inositol polyphosphate kinases (IPKs) that we discovered are involved in the conversion of inositol 1,4,5- trisphosphate (IP3) to higher IP messengers (such as IP4, IP5, IP6 and inositol pyrophosphates - PP-IPs). Our studies of the IPKs, supported by this grant in previous years, have led to the definition of novel messenger roles for these lipid-derived IP chemical codes in the regulation of gene expression/transcription, mRNA export, telomere maintenance, organism development and most recently a role for inositol pyrophosphates in nutrient signaling. In this proposal we will focus primarily on two kinases, IPMK (also referred to as IPK2) and the newly discovered VIP1, a novel IP6/IP7 kinase, another IPK implicated in the control of gene expression in response to nutrient change and cell morphology. We seek to accomplish two major objectives: 1) elucidate the mechanisms of IPMK-mediated control of gene expression, growth control and cell death; and 2) understand the roles of diphosphoinositol phosphates, also known as inositol pyrophosphates, through studies of the exciting new evolutionarily conserved VIP1-like class of IP6/IP7 kinase. Overall, this work will further characterize IPK-dependent signaling pathways and the receptors that decode these important cellular regulators. We envision that the IPKs modulate an IP code. By analogy to a nucleotide code, we suggest that each IP species represents a base. Thus far over 20 IP bases generated by IPKs have been identified in cells and the number continues to grow. Through altering the patterns and levels of each IP base, we suggest that a cell may generate a combinatorially complex dynamic code capable of enhancing signaling specificity. Our studies of the IP code will likely provide new insights into organism development, cellular growth control and nutrient adaptation with relevance to public health. Public Health Relevance: Our proposal seeks to elucidate lipid-derived inositol phosphate cellular signal transduction pathways. Defects in the kinases and phosphatases that regulate an inositol phosphate signaling code result in human disease and defects in growth control, adaptation and organism development. Understanding these essential enzymes will provide significant insights into human cell biology and improve public health through basic science research.

描述（由申请人提供）：该赠款的长期目标是阐明肌醇多磷酸盐（IP）信号通路，并确定细胞使用它们来引起选择性细胞内反应的机制。我们采用了一种分子方法来理解这些途径，并共同克隆并确定了与IP Messenger代谢有关的许多酶的功能。该提案的重点是我们发现的肌醇聚磷酸激酶（IPK）参与了肌醇1,4,5-三磷酸（IP3）转化为较高的IP Messenger（例如IP4，IP5，IP6和Inositol pyrophophathate-PP-PP-IPS）。我们对IPK的研究在前几年得到了这笔赠款的支持，导致了这些脂质衍生的IP化学代码在基因表达/转录，mRNA输出，端粒维持，生物体的发展，最近以及最近在营养信号中的肌醇磷酸磷酸盐的作用的定义。在此提案中，我们将主要关注两种激酶，即IPMK（也称为IPK2）和新发现的VIP1，一种新型的IP6/IP7激酶，这是另一个IPK，其中涉及对基因表达的响应，响应营养变化和细胞形态。我们试图实现两个主要目标：1）阐明IPMK介导的基因表达，生长控制和细胞死亡的控制的机制； 2）通过研究激动人心的新进化保守的IP6/IP7激酶，了解二磷酸肌醇磷酸盐（也称为肌醇焦磷酸盐）的作用。总体而言，这项工作将进一步表征IPK依赖性信号通路和解码这些重要细胞调节剂的受体。我们设想IPK调制IP代码。通过类似于核苷酸代码，我们建议每个IP物种代表一个基础。到目前为止，IPK产生的20多个IP碱基已在细胞中鉴定出来，数量继续增长。通过更改每个IP碱基的模式和级别，我们建议单元格可能会生成能够增强信号特异性的组合复杂的动态代码。我们对IP代码的研究可能会为有机体开发，细胞生长控制和与公共卫生相关的营养适应提供新的见解。公共卫生相关性：我们的提议旨在阐明脂质衍生的磷酸磷酸磷酸细胞信号转导途径。调节肌醇磷酸盐信号代码的激酶和磷酸酶的缺陷导致人类疾病和生长控制，适应和生物体发育的缺陷。了解这些基本酶将为人类细胞生物学提供重要的见解，并通过基础科学研究改善公共卫生。