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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=760827
• 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，在其发育和维持中起关键作用。小胶质细胞在生命的最初几周内增殖，以达到通过细胞分裂（增殖）、细胞死亡和相邻小胶质细胞之间的细胞间排斥而在整个生命期间维持的密度。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的，并在成年后持续存在。研究表明，IL 1细胞因子可调节小胶质细胞增殖。当我建立我的新实验室时，我将制定一个长期计划，以了解小胶质细胞密度是如何1）最初在发育中实现的，以及2）在整个成年生活中持续的。我的短期目标是确定是否IL 1细胞因子，也许还有其他因素调节小胶质细胞在发育和成人大脑的增殖。我将使用可用的小鼠模型来确定哪些因素促进小胶质细胞增殖。目的1：鉴定小胶质细胞发育过程中参与增殖的IL-1细胞因子。小胶质细胞在出生后的前两周内广泛增殖。在出生后早期，什么样的因子负责驱动小胶质细胞增殖，目前还知之甚少，但小胶质细胞确实在损伤期间响应于称为细胞因子的几种因子（包括IL 1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IL 1细胞因子和受体的小鼠大脑发育中的小胶质细胞增殖。目的2：确定成人体内稳态小胶质细胞密度是否需要IL 1细胞因子。小胶质细胞密度如何在整个生命过程中维持尚不清楚，但一种可能性是白细胞介素1细胞因子促进缓慢进行的增殖。为了评估这种可能性，一名研究生将评估缺乏IL 1细胞因子和受体的成年小鼠中小胶质细胞的增殖和细胞死亡。这一目标允许评价小胶质细胞是否需要持续的IL 1细胞因子来维持增殖。目的3：确定小胶质细胞增殖所必需的其他因素。在我的博士后工作中，我确定了潜在的小胶质细胞增殖诱导因子。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。我们的工作将是第一个确定在发育和成人大脑中调节其生产的因素。这些结果将促进我们对小胶质细胞生产的理解，有助于在整个生命过程中建立和维护大脑。