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TNFR2 Sex Differences and EAE

TNFR2 性别差异和 EAE

基本信息

批准号：
10384115
负责人：
John Roland Bethea
金额：
$ 37.88万
依托单位：
DREXEL UNIVERSITY
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：
2021-12-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10384115
关键词：
ATF6 gene Agonist Cell Death Cells Coupled Data Disease Disease Progression Experimental Autoimmune Encephalomyelitis Female Genes Genetic Goals Gonadal Steroid Hormones Immune response In Vitro Inflammation Inflammatory Response Knockout Mice Ligation Link Mediating Mediator of activation protein Motor Multiple Sclerosis Mus Myelin Natural regeneration Nerve Degeneration Neuraxis Neuroimmune Neuroimmune system Neurologic Neurons Oligodendroglia Pathology Pathway interactions Pharmacology Physiological Predisposition Process Protein Biosynthesis Proteins Publishing Quality Control Recovery of Function Regenerative response Role Series Sex Bias Sex Chromosomes Sex Differences Signal Transduction Stress TNFRSF1B gene Testing Therapeutic Therapeutic Effect Work XBP1 gene base burden of illness hormonal signals in vivo male motor disorder motor function improvement motor impairment motor recovery neuroinflammation neuropathology novel painful neuropathy programs remyelination repaired response sex transcriptome sequencing

项目摘要

Abstract The susceptibility to Multiple Sclerosis (MS) is believed to be due in part to neuroinflammation and disease burden linked to neurodegeneration. It is well established that females have a more robust immune response than males however, neurodegeneration and disease progression are more sever in males. Thus, in the context of MS, this raises an intriguing question. Do females, by virtue of having a more robust inflammatory responses, have endogenous protection/repair mechanisms to protect the central nervous system (CNS) from inflammation induced pathology, that males do not have or that are not as effective in males? This proposal is based upon extensive preliminary and published data demonstrating that tmTNF/TNFR2 signaling in females, but not males, significantly improves motor function and reduces neuropathology in EAE by activating endogenous repair programs in neurons and oligodendrocytes. Based upon these and other results, our first experimental goal is to interrogate sex differences in tmTNF/TNFR2 induced improvements in motor function and neuropathology. Further, we have very novel pharmacological and genetic data that ligation of TNFR2 on both neurons and oligodendrocytes induce regenerative responses, through IRE1-dependent mechanisms. Based upon these and additional data our second experimental goal is to investigate the intersection between TNFR2/IRE1 signaling and to determine if the therapeutic effects of TNFR2 activation are dependent upon IRE1 activation. These goals will be tested in the following aims: Specific Aim 1: Investigate the sex-specific effects of tmTNF/TNFR2 signaling in the improvement of motor function and neuropathology. A) We will investigate the role of sex hormones in tmTNF/TNFR2 signaling in the improvement of motor function and neuropathology in male and female mice. B) We will investigate the role of sex chromosomes in tmTNF/TNFR2 signaling in the improvement of motor function and neuropathology in male and female mice. Specific Aim 2: Investigate TNFR2 induced endogenous repair mechanisms in male and female mice. A) We will interrogate TNFR2 induced endogenous repair mechanisms oligodendrocytes and determine if they are required for motor recovery in females. B) We will interrogate TNFR2 induced endogenous repair mechanisms neurons and determine if they are required for motor recovery in females, in vivo and in vitro.

抽象的多发性硬化症 (MS) 的易感性被认为部分是由于神经炎症造成的以及与神经退行性变相关的疾病负担。众所周知，女性拥有更强健的体质免疫反应比男性强，然而，神经退行性变和疾病进展在男性中更为严重男性。因此，在多发性硬化症的背景下，这提出了一个有趣的问题。做女性，凭借拥有更强烈的炎症反应，具有内源性保护/修复机制来保护炎症引起的病理学中枢神经系统（CNS），男性没有或有对男性没有那么有效吗？该提案基于广泛的初步和已发布的数据证明女性而非男性中的 tmTNF/TNFR2 信号传导可显着改善运动能力通过激活神经元中的内源性修复程序来发挥功能并减少 EAE 中的神经病理学少突胶质细胞。基于这些和其他结果，我们的第一个实验目标是询问性别 tmTNF/TNFR2 的差异导致运动功能和神经病理学的改善。此外，我们具有非常新颖的药理学和遗传数据，即 TNFR2 在神经元和少突胶质细胞通过 IRE1 依赖性机制诱导再生反应。基于这些和其他数据我们的第二个实验目标是研究之间的交叉点 TNFR2/IRE1 信号转导并确定 TNFR2 激活的治疗效果是否具有依赖性 IRE1 激活后。这些目标将在以下目标中进行测试：具体目标 1：研究 tmTNF/TNFR2 信号传导在改善运动功能和神经病理学。 A) 我们将研究性激素在 tmTNF/TNFR2 信号传导中对运动能力改善的作用雄性和雌性小鼠的功能和神经病理学。 B) 我们将研究性染色体在 tmTNF/TNFR2 信号传导中在改善运动能力方面的作用雄性和雌性小鼠的功能和神经病理学。具体目标 2：研究 TNFR2 在雄性和雌性小鼠中诱导的内源性修复机制。 A) 我们将询问 TNFR2 诱导的少突胶质细胞内源性修复机制，并确定是否它们是女性运动恢复所必需的。 B) 我们将询问 TNFR2 诱导的神经元内源性修复机制，并确定它们是否女性体内和体外运动恢复所需的。