The Role of Inositol Signaling in Human Disease

描述（改编自申请人的摘要）：本项目的长期目标 该项目旨在阐明不同的细胞外刺激是如何引起选择性 通过激活肌醇多磷酸（IP）的细胞反应 信号通路IP信号通路的缺陷导致疾病状态 如人眼脑肾综合征或Lowe综合征。有30多个IP 其中大部分分子还没有被作为信使进行研究。是我们 假设这样的IP，指定为“孤儿”，可能具有重要的信令， 角色为了支持这一点，我们最近定义了新的信号作用， 孤儿IP调节膜运输、细胞骨架组织、基因 表达和mRNA输出。此外，我们还发现了一个锂族 与躁狂抑郁症相关的目标。一个新的主题出现在 我们的工作是，某些肌醇信号通路被划分为 直接影响细胞核的功能。该项目的重点是 孤儿IF信使在调节，膜运输，基因 表达和信使RNA输出。我们还试图描述一个新的家庭 I磷酸酶是锂相关双极的潜在靶点， 疾病IP 5和IP 6是普遍存在的肌醇磷酸盐，直到我们最近 工作没有明确定义的信号分子的作用。我们已经证明 PLC产生IP 3，然后通过两个IP依次磷酸化为IP 6， 激酶，核双特异性IP 3/IP 4激酶（Ipk 2），和核 包膜/孔复合物定位于IP 5 2-激酶（Ipkl）。ipk 2 p显示相同 一种已知的转录因子，提供IP信号传导的关键直接联系， 基因表达。了解Ipk 2 p介导的靶基因调控 转录复合物，IP受体和定位的机制 IP 4/IP 5介导的转录变化的产生将有助于定义如何 核IP信号调节细胞生长和发育。Ipklp的研究 发现了IP 6在信使RNA输出中的作用 受体、相关成分和调节机制将被 有助于阐明IP信号传导如何调节信使RNA输出。我们 还计划评估IP 5和IP 6在哺乳动物系统中的功能。他们 与酵母中的功能相似吗我们计划分离和克隆 编码在哺乳动物组织中相互转化IP 5和IP 6的酶， IP 5 2-激酶和IP 6 2-磷酸酶，以确定 这些代谢物受到控制。此外，我们计划研究第一个 具有两个自主活性位点的双功能肌醇脂质磷酸酶， 一种是多磷酸肌醇磷酸酶，另一种是类似于 在劳氏综合征中突变的OCRL-1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.