The Role of Inositol Signaling in Human Disease

描述(改编自申请人的摘要)：这是一个长远的目标 该项目旨在阐明不同的细胞外刺激如何引发选择性 肌醇多聚磷酸(IP)激活引起的细胞反应 信号通路。IP信号通路缺陷导致疾病状态 如人类眼-脑-肾综合征或洛威综合征。有30多个IP 分子，其中大部分还没有作为信使进行研究。这是我们的 假设这样的IP，被指定为“孤儿”，可能有重要的信号 角色。为了支持这一点，我们最近定义了新的信号角色 孤儿IP对膜转运、细胞骨架组织、基因的调控 表达和信使核糖核酸输出。此外，我们还发现了一个锂家族 与躁郁症相关的目标。一个新的主题出现在 我们的工作是将某些肌醇信号通路划分为 并直接影响核的功能。本项目的重点是 孤儿IF信使在调节、膜转运、基因表达中的作用 表达和信使RNA输出。我们还试图描述一个新的家庭 是锂与双极相关的潜在靶标的I磷酸酶 疾病。IP5和IP6是普遍存在的肌醇磷酸盐，直到我们最近的 功没有明确定义为信号分子的角色。我们已经证明了 PLC产生IP3，然后由两个IP依次将其磷酸化为IP6 一种核内双特异性IP3/IP4激酶(Ipk2)和核 包膜/孔复合体定位的IP5 2-激酶(Ipk1)。Ipk2p显示完全相同 到一个已知的转录因子，该转录因子提供了IP信号和 基因表达。了解Ipk2p介导的靶基因调控 转录复合体、IP受体及其定位机制 IP4/IP5的产生将有助于定义转录的变化 核IP信号调节细胞的生长和发育。对IPKLP的研究有 发现IP6产物在信使RNA出口鉴定中的作用 受体、涉及的成分和调节机制将是 有助于阐明IP信号如何调节信使RNA输出。我们 还计划评估IP5和IP6在哺乳动物系统中的功能。他们是不是 在酵母中有类似的功能吗？我们计划分离和克隆cDNAs 编码在哺乳动物组织中相互转换IP5和IP6的酶，即 为了确定IP5 2-激酶和IP6 2-磷酸酶如何产生 这些代谢物是受控制的。此外，我们计划研究第一个 具有两个自主活性部位的双功能肌醇脂磷酸酶， 一种是多磷肌醇磷酸酶，另一种是类似于 在洛威综合征中突变的OCRL-L蛋白。

DESCRIPTION(adapted from applicant's abstract): The long-range goal of this project is to elucidate how diverse extracellular stimuli elicit selective cellular responses through the activation of inositol polyphosphate (IP) signaling pathways. Defects in IP signaling pathways result in disease states such as human oculocerebrorenal syndrome or Lowe syndrome. There are over 30 IP molecules the majority of which have not been studied as messengers. It is our hypothesis that such IPs, designated a "orphans," may have important signaling roles. In support of this, we have recently defined novel signaling roles for orphan IPs in regulating membrane trafficking, cytoskeletal organization, gene expression and mRNA export. Additionally, we have uncovered a family of lithium targets with relevance to manic depressive disease. A new theme emerging from our work is that certain inositol signaling pathways are compartmentalized to the nucleus and directly effect nuclear function. This project focuses on the roles of orphan IF messengers in regulating, membrane trafficking, gene expression and messenger RNA export. We also seek to characterize a new family of I phosphatases that are potential targets of lithium relevance to bipolar disease. IP5 and IP6 are ubiquitous inositol phosphates that until our recent work had no clearly defined roles as signaling molecules. We have shown that PLC produces IP3, which is then sequentially phosphorylated to IP6 by two IP kinases, a nuclear dual-specificity IP3/IP4 kinase (Ipk2), and nuclear envelope/pore complex localized IP5 2-kinase (Ipkl). Ipk2p reveal is identical to a known transcription factor providing a crucial direct link of IP signaling and gene expression. Understanding the target genes regulated by Ipk2p-mediated transcription complexes, the IP receptors and the mechanism by which localized production of IP4/IP5 mediate changes in transcription will help define how nuclear IP signals regulate cell growth and development. Studies of Ipklp have uncovered a role for IP6 production in messenger RNA export Identification of the receptors, components involved and mechanisms of regulation will be instrumental in elucidating how IP signaling regulates messenger RNA export. We also plan to evaluate the function of IP5 and IP6 in mammalian systems. Do they serve a similar function to that in yeast? We plan to isolate and clone cDNA's encoding the enzymes that interconvert IP5 and IP6 in mammalian tissues namely IP5 2-kinase and IP6 2-phosphatase in order to determine how production of these metabolites is controlled. In addition, we plan to study the first dual-functional inositol lipid phosphatase with two autonomous active sites, one a polyphosphoinositide phosphatase and the other a 5-phosphatase similar to the OCRL-l protein that is mutated in Lowe syndrome.