Advancing a comparative understanding of the molecular regulation of solute carriers and channels

促进对溶质载体和通道的分子调节的比较理解

• 批准号: RGPIN-2021-02743
• 负责人: Loewen, Matthew
• 金额: $ 3.06万
• 依托单位: University of Saskatchewan
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=741808
• 关键词: Advancing; comparative; understanding; molecular; regulation

A living cell moves salts, amino acids and glucose across its lipid membranes through solute carriers and ion channels. Plants and animals create tissues from cells with specific carriers and channels to maintain osmotic balance, as well as move nutrients into/waste out of the organism. These processes can be greatly altered by environmental factors (eg. pathogens, toxic irritants, nutrient availability). Despite the ubiquitous nature of these responses, the mechanism by which carriers and channels are regulated by such stimulus remains unresolved in most systems. Thus, the long-term goal of my program is to develop a comparative understanding of the mechanisms by which carriers and channels are regulated by environmental stimulus. In this context, during the five-year term of this Discovery Grant, a medium-term goal of defining the cellular mechanisms underlying the pig specific pathogen Brachyspira hyodysenteriae and its alterations of colonic ion transport to cause diarrhea will be undertaken. More specially, we will assess how the diarrhea develops over time with changes in solute carriers and ion channels. In addition, we will also look at structure and function of a protein from the bacteria that may cause some of the changes seen over time. Finally, we will take an in-depth look into the cell signalling events induced by the bacteria within the cell that may contribute to the changes seen. Overall, this will contribute to the longer-term goal of the program, looking for similarities in pathways/kinases mechanisms of activation/inaction, trafficking and expression during exposure to environmental effectors across various animal and plant carrier and ion channel systems. But, in the short-term the work will give insight into the regulation of the pig's colonic epithelial transport, but also define cellular and biophysical mechanisms by which a bacterium that has plagued the swine industry for 100 years can cause disease. In addition, this project will yield unique cross disciplinary training of multiple highly qualified personnel (HQP) in physiology, biochemistry and cell biology, skills which are highly desirable and sought after by pharmaceutical industry employers. But, for Canada, a more complete basic understanding of how the bacterium causes diarrhea (agent's proteins and host's cellular response) is needed to allow us to move forward armed with new knowledge to produce new treatments and eradication strategies. This would have a significant economic impact for swine producers in Canada, allowing them to better compete in a global market.

活细胞通过溶质载体和离子通道将盐、氨基酸和葡萄糖转移到其脂膜上。植物和动物通过特定的载体和通道从细胞中产生组织，以维持渗透平衡，并将营养物质转移到生物体内/从有机体中排出。这些过程可能会被环境因素极大地改变(例如，病原体、有毒刺激物、营养可获得性)。尽管这些反应无处不在，但在大多数系统中，载体和渠道受到此类刺激的机制仍未解决。因此，我的项目的长期目标是对环境刺激对载体和渠道进行监管的机制有一个比较的了解。在此背景下，在这项发现拨款的五年任期内，将实施一个中期目标，以确定猪特定病原体猪瘟短螺旋体的细胞机制及其引起腹泻的结肠离子转运的变化。更具体地说，我们将评估随着时间的推移，随着溶质载体和离子通道的变化，腹泻是如何发展的。此外，我们还将研究细菌蛋白质的结构和功能，这些蛋白质可能会导致随着时间的推移而出现的一些变化。最后，我们将深入研究由细胞内的细菌诱导的细胞信号事件，这些事件可能有助于所看到的变化。总体而言，这将有助于该计划的长期目标，寻找在暴露于各种动植物载体和离子通道系统的环境效应器期间，激活/不作用、运输和表达的通路/激酶机制的相似性。但是，在短期内，这项工作将深入了解猪的结肠上皮运输的调节，并确定细胞和生物物理机制，通过这些机制，一种困扰养猪业100年的细菌可以导致疾病。此外，该项目还将在生理学、生物化学和细胞生物学方面为多名高素质人员(HQP)提供独特的跨学科培训，这些技能是制药业雇主非常希望和追捧的。但是，对于加拿大来说，需要对细菌如何引起腹泻(病原体的蛋白质和宿主的细胞反应)有更全面的基本了解，以便让我们能够利用新的知识向前迈进，以产生新的治疗方法和根除策略。这将对加拿大的生猪生产商产生重大的经济影响，使他们能够更好地在全球市场上竞争。