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Stress effects on microglia activation: Sex matters

压力对小胶质细胞激活的影响：性别很重要

基本信息

批准号：
10451100
负责人：
Georgia E Hodes
金额：
$ 38.59万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10451100
关键词：
Affect Alzheimer&apos s Disease Anti-Inflammatory Agents Astrocytes Behavior Behavioral Bilateral Brain Brain Diseases CX3CL1 gene Cells Chemical Engineering Classification Communities Data Disease Dose Eating Emotional Enzyme-Linked Immunosorbent Assay Exposure to FDA approved Female Formulation Gene Expression Profile Genetic Transcription Human Immune Immune system In Vitro Individual Inflammatory Infusion procedures Interferon Type II Interleukin-4 Label Ligands Literature Measures Mental Depression Mental disorders Methods Microglia Molecular Morphology Mus Neurons Nucleus Accumbens Operative Surgical Procedures Parkinson Disease Phagocytosis Pharmaceutical Preparations Pharmacology Phenotype Phosphatidylserines Polymer Chemistry Polymers Positioning Attribute Predisposition Prefrontal Cortex Process Production Proteins Recombinant Cytokines Reporting Research Rodent Sampling Schizophrenia Sex Bias Sex Differences Signal Transduction Social Interaction Specificity Stress Symptoms Testing Time Tissues Transcriptional Activation Validation Visual Woman autism spectrum disorder behavior test behavioral response cell type cohort cytokine design dosage emotion regulation experience experimental study hedonic immune activation in vivo male men nano-string nanomedicine nanoparticle nanoparticle exposure particle pathogen pleasure receptor resilience sex social targeted delivery tool

项目摘要

Microglia activation is a process that has been identified throughout the brain in many human psychiatric illnesses including depression, schizophrenia, autism spectrum disorder, Parkinson’s and Alzheimer’s disease. All of these disorders include symptoms such as decreased experience of pleasure or social activity and increased threat appraisal. Additionally, all of these disorders have different rates of occurrence in men and women. We have little information on why microglia are aberrantly activated and the consequences of this activation on an individual. When activated, microglia can produce pro-inflammatory signals to protect the brain from pathogens but that also can damage host tissue. Other microglia when activated produce anti-inflammatory signals. Microglia directly interact with neurons but we don’t know which forms of activation change how the neurons and their circuit’s function. We currently lack research tools that will allow us to drive microglia activation in a region-specific manner without directly affecting other cell types. The proposed studies will develop and test a new tool set of immune directed nanoparticles. These nanoparticles are designed to only be taken up by microglia and shift them to a pro-inflammatory or anti-inflammatory state. We will test the ability of these nanoparticles to shift the cytokines released from microglia and the transcriptional state of the activated microglia within the nucleus accumbens. Once dose and immune endpoints are fully validated, we will test the ability of nanoparticles to modulate the impact of variable stress on behavior in tests that measure threat appraisal, hedonic experience and social interaction. The experiments outlined in this proposal will provide us with a new method to produce and track specific forms of microglia activation. The particles used in this proposal are, by design, exemplary cases that can be made from a diverse range of polymers commonly utilized in FDA-approved nanomedicine formulations. Completion of this project will provide us with robust and accurate design criteria for producing particles that can effectively deliver cytokines and other drugs specifically to microglia in vivo and will be made available to the greater scientific community. Once developed these studies will inform us on how to harness the immune system to identify and treat psychiatric illness.

小胶质细胞激活是一个在许多人类精神疾病（包括抑郁症、精神分裂症、自闭症谱系障碍、帕金森病和阿尔茨海默病）的整个大脑中被确定的过程。所有这些疾病都包括一些症状，如快乐或社交活动体验减少，威胁评估增加。此外，所有这些疾病在男性和女性中的发生率不同。我们对小胶质细胞异常激活的原因以及这种激活对个体的影响知之甚少。当被激活时，小胶质细胞可以产生促炎信号，以保护大脑免受病原体的侵害，但这也会损害宿主组织。其他小胶质细胞在激活时产生抗炎信号。小胶质细胞直接与神经元相互作用，但我们不知道哪种形式的激活会改变神经元及其回路的功能。我们目前缺乏研究工具，使我们能够在不直接影响其他细胞类型的情况下以区域特异性方式驱动小胶质细胞激活。拟议的研究将开发和测试一套新的免疫定向纳米粒子工具。这些纳米颗粒被设计成只被小胶质细胞吸收，并将它们转变为促炎或抗炎状态。我们将测试这些纳米颗粒转移从小胶质细胞释放的细胞因子的能力以及激活的小胶质细胞在核内的转录状态。一旦剂量和免疫终点得到充分验证，我们将在测量威胁评估、享乐体验和社会互动的测试中测试纳米颗粒调节可变压力对行为的影响的能力。该提案中概述的实验将为我们提供一种新的方法来产生和跟踪特定形式的小胶质细胞激活。通过设计，该提案中使用的颗粒是可以由FDA批准的纳米药物制剂中常用的各种聚合物制成的示例性情况。该项目的完成将为我们提供强大而准确的设计标准，用于生产可以有效地将细胞因子和其他药物特异性地递送到体内小胶质细胞的颗粒，并将提供给更大的科学界。这些研究一旦发展起来，将告诉我们如何利用免疫系统来识别和治疗精神疾病。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sex differences in depression: An immunological perspective.

抑郁症的性别差异：免疫学角度。

DOI：
10.1016/j.brainresbull.2023.02.016
发表时间：
2023-05
期刊：
Brain research bulletin
影响因子：
3.8
作者：
通讯作者：

Sex and region-specific effects of variable stress on microglia morphology.

DOI：
10.1016/j.bbih.2021.100378
发表时间：
2021-12
期刊：
Brain, behavior, & immunity - health
影响因子：
0
作者：
Tsyglakova M;Huskey AM;Hurst EH;Telep NM;Wilding MC;Babington ME;Rainville JR;Hodes GE
通讯作者：
Hodes GE