Role of Iron in the Regulation of PTPs: Impact on Cell Signaling and Functions

铁在 PTP 调节中的作用：对细胞信号传导和功能的影响

• 批准号: RGPIN-2018-03849
• 负责人: Olivier, Martin
• 金额: $ 3.64万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=661192
• 关键词: Role; Iron; Regulation; PTPs; Impact

* * 0* 0* 1* 338* 1860* McGill University* 15* 4* 2194* 14.0* * * 96* 800x600* *** * Normal* 0* * * 21* * * false* false* false* * FR-CA* JA* X-NONE* * * * * * * * * * * * * * * * * * * * * * * * ** * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *** **** /* Style Definitions */*table.MsoNormalTable* {mso-style-name:"Tableau Normal";* mso-tstyle-rowband-size:0;* mso-tstyle-colband-size:0;* mso-style-noshow:yes;* mso-style-priority:99;* mso-style-parent:"";* mso-padding-alt:0cm 5.4pt 0cm 5.4pt;* mso-para-margin:0cm;* mso-para-margin-bottom:.0001pt;* mso-pagination:widow-orphan;* font-size:10.0pt;* font-family:Calibri;}****The goal of this research program is to study the implication of iron in*the regulation of a family of enzyme named protein tyrosine phosphatase (PTP).*PTPs play a critical role in the regulation of macrophage (MO) functions by*influencing and controlling their fine balance with kinases. By*dephosphorylating kinase substrates, PTPs can influence the level of kinase*activities and consequently the MO functions and innate immune response.*Whereas oxidation plays an important role in the regulation of PTPs and this*via the action of ROS, we have recently discovered that iron could play a*critical in the regulation of PTPs, under the form of a mononuclear dicitrate*iron complex precisely fitting itself within PTP's catalytic pocket inhibiting*their activity. We believe that such capacity in the context MO function*regulations and particuolarly the ones involved in innate immune response could*plays a critical role to control homeostatic and abnormal cellular*conditions. The actual grant proposal is*designed to study the specificity of this iron species toward MO PTPs (Aim 1)*and to analyze whether this iron-mediated modulation of PTPs happens in vivo*(Aim 2). In Aim 1, we propose to determine whether all MO PTPs (classic, DUS*PTPs and RPTPs) are similarly regulated by mononuclear ion-citrate, as well as*to follow their sub-cellular mobilization to various compartments in order to*interact with specific substrates involved in the signaling events concurring*to regulate innate immunity in response to inflammatory agonists. In Aim 2, the findings stemming from in vitro*evaluation proposed above, will be further tested in vivo using specific*inhibitors for PTPs, inoculation of iron-dextran, as well as to use models with*physiologically iron defective mice. Impact of those augmented or reduced*availability or iron in vivo will be monitored at cellular, molecular and*innate immunity levels. ***Findings stemming from these studies could permit in a near future to*develop new ways to render more resistant animals from industry toward*infectious agents by reinforcing their innate immune system, and this by adding*newly identified mononuclear dicitrate iron to their diet.***

**0*0*1*338*1860*麦吉尔大学*15*4*2194*14.0***96*800x600***正常*0***21***FALSE**FR-CA*JA*X-NONE******/**mso-tstyle-rowband-size：0；*mso-tstyle-colband-size：0；*mso-style-noshow：是；*mso-style-first：99；*mso-style-parent：“”；*mso-pding-alt：0 cm 5.4pt 0 cm 5.4pt；*mso-para-mark：0 cm；*mso-para-edge-Bottom：.0001pt；*mso-Page：Wow-Orban；*Font-Size：10.0pt；*Font-Family：Calibri；*本研究计划的目的是研究铁在一种名为蛋白酪氨酸磷酸酶(PTP)的酶家族中的调节作用。蛋白酪氨酸磷酸酶通过影响和控制其与蛋白酪氨酸磷酸酶的精细平衡，在巨噬细胞(MO)的功能调节中发挥关键作用。通过去磷酸化激酶底物，PTPs可以影响激酶活性水平，从而影响MO功能和先天性免疫反应。尽管氧化在PTPs的调节中发挥着重要作用，这是通过ROS的作用，但我们最近发现，铁在PTPs的调节中发挥了关键作用，在PTP的催化口袋中，铁以单核双柠檬酸盐的形式恰好适合自己，抑制了它们的活性。我们认为，在MO功能调节的背景下，这种能力，特别是参与先天免疫反应的能力，可以*在控制体内平衡和异常细胞*条件方面发挥关键作用。实际的拨款提案旨在研究这种铁物种对MO PTPs的特异性(目标1)*并分析这种铁介导的PTPs的调节是否在体内发生*(目标2)。在目标1中，我们建议确定是否所有的MO PTPs(Classic，DUS*PTPs和RPTPs)都受到单核离子柠檬酸盐的类似调节，以及*跟随它们的亚细胞动员到不同的隔室，以便与参与同时发生的信号事件的特定底物相互作用，以调节对炎症激动剂的先天性免疫。在目标2中，上述体外评估的结果将使用PTPs的特定抑制剂、接种葡聚糖铁以及使用生理性铁缺陷小鼠的模型进行进一步的体内测试。将在细胞、分子和先天免疫水平上监测体内铁的有效性增强或降低的影响。*这些研究的发现可能会在不久的将来*开发新的方法，通过加强动物的天然免疫系统，并在它们的饮食中添加*新发现的单核二柠檬酸盐铁，使工业中的动物对*传染病具有更强的抵抗力。*