Cytokine involvement in microglia proliferation

细胞因子参与小胶质细胞增殖

• 批准号: RGPIN-2019-04533
• 负责人: Plemel, Jason
• 金额: $ 2.19万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=683408
• 关键词: Cytokine; involvement; microglia; proliferation

Microglia are the resident immune cells of the brain and spinal cord with critical roles in their development and maintenance. Microglia proliferate in the first weeks of life to achieve a density that is maintained throughout life by cell division (proliferation), cell death, and cell-to-cell repulsion between adjacent microglia. Currently, it is unclear how this microglia density is initially achieved developmentally and sustained in adulthood. Research suggests that the IL1 cytokines may regulate microglia proliferation. As I establish my new laboratory, I will develop a long-term program to understand how microglia density is 1) initially achieved in development and 2) sustained throughout adult life. My short-term objectives are to determine if IL1 cytokines and perhaps also other factors regulate microglia proliferation in the developing and adult brain. I will use available mouse models to determine what factors promote microglia proliferation.******AIM 1: Identify the IL-1 cytokines responsible for microglia proliferation during development. Microglia proliferate extensively in the first two weeks after birth. Little is known on what factor(s) is(are) responsible for driving microglia proliferation during this early postnatal period, but microglia do proliferate in response to several factors called cytokines during injury including IL1 cytokines. To answer this question, a graduate student will measure microglia proliferation in the developing brain of mice deficient for IL1 cytokines and receptors.******AIM 2: Determine whether homeostatic microglia densities require IL1 cytokines in adults. How microglia density is maintained throughout life is unknown, but one possibility is that interleukin 1 cytokines promote slow ongoing proliferation. To evaluate this possibility, a graduate student will assess microglia proliferation and cell death in adult mice deficient for IL1 cytokines and receptors. This aim allows an appreciation of whether microglia require ongoing IL1 cytokines to sustain proliferation.******AIM 3: Identify other factors that are necessary for microglia proliferation. In my postdoctoral work, I identified potential microglia proliferation-inducing factors. A graduate student will screen these candidate factors to identify new molecules that promote microglia proliferation. The graduate student will screen these factors with purified microglia cultures and determine their capacity to stimulate microglia proliferation in vitro. They will also assess whether these new factors promote microglia proliferation in the developing brain. This aim will identify new factors that stimulate microglia proliferation.******Microglia are an essential cell to healthy brain function. Our work will be the first to identify factors that regulate their production in the developing and adult brain. The outcomes will advance our understanding of microglia production contribute to building and maintaining the brain throughout life.*****

小胶质细胞是大脑和脊髓的常驻免疫细胞，在其发育和维持中发挥着关键作用。小胶质细胞在生命的最初几周内增殖，通过细胞分裂（增殖）、细胞死亡和相邻小胶质细胞之间的细胞间排斥，达到终生维持的密度。目前，尚不清楚这种小胶质细胞密度最初是如何在发育过程中实现并在成年期维持的。研究表明 IL1 细胞因子可能调节小胶质细胞增殖。当我建立新实验室时，我将制定一个长期计划，以了解小胶质细胞密度是如何 1）在发育过程中最初实现的以及 2）在整个成年生活中持续存在的。我的短期目标是确定 IL1 细胞因子以及其他因素是否调节发育中和成人大脑中的小胶质细胞增殖。我将使用现有的小鼠模型来确定哪些因素促进小胶质细胞增殖。******目标 1：确定在发育过程中负责小胶质细胞增殖的 IL-1 细胞因子。小胶质细胞在出生后的前两周内广泛增殖。我们对哪些因素负责在产后早期驱动小胶质细胞增殖知之甚少，但小胶质细胞确实会在损伤期间响应多种称为细胞因子的因素（包括 IL1 细胞因子）而增殖。为了回答这个问题，一名研究生将测量缺乏 IL1 细胞因子和受体的小鼠发育中的大脑中小胶质细胞的增殖情况。******目的 2：确定成人中稳态小胶质细胞密度是否需要 IL1 细胞因子。小胶质细胞密度在整个生命过程中如何维持尚不清楚，但一种可能性是白细胞介素 1 细胞因子促进缓慢的持续增殖。为了评估这种可能性，研究生将评估缺乏 IL1 细胞因子和受体的成年小鼠的小胶质细胞增殖和细胞死亡。这一目标可以了解小胶质细胞是否需要持续的 IL1 细胞因子来维持增殖。******目标 3：确定小胶质细胞增殖所需的其他因素。在我的博士后工作中，我发现了潜在的小胶质细胞增殖诱导因素。研究生将筛选这些候选因子，以确定促进小胶质细胞增殖的新分子。研究生将用纯化的小胶质细胞培养物筛选这些因子，并确定它们在体外刺激小胶质细胞增殖的能力。他们还将评估这些新因素是否促进发育中大脑中小胶质细胞的增殖。这一目标将确定刺激小胶质细胞增殖的新因素。******小胶质细胞是健康大脑功能的重要细胞。我们的工作将首先确定在发育中和成人大脑中调节其产生的因素。这些结果将增进我们对小胶质细胞生成有助于终生构建和维持大脑的理解。*****