TNFR2 Sex Differences and EAE

TNFR2 性别差异和 EAE

• 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
• 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

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.

摘要 多发性硬化症(MS)的易感性被认为部分是由于神经炎症 以及与神经退化有关的疾病负担。众所周知，女性有更健壮的 然而，免疫反应比男性更严重，神经退化和疾病进展更严重 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。女性，因为有一种 更强大的炎症反应，具有内源性保护/修复机制，以保护 中枢神经系统(CNS)由炎症引起的病理，男性没有或 对男性不是很有效吗？这项建议是基于广泛的初步数据和已公布的数据。 表明tmTNF/TNFR2信号在女性，而不是男性，显著改善运动 通过激活神经元和神经细胞的内源性修复程序来发挥功能并减少EAE的神经病理 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审讯性 TmTNF/TNFR2的差异导致运动功能和神经病理的改善。此外，我们 有非常新的药理学和遗传学数据表明，连接TNFR2对神经元和 少突胶质细胞通过依赖IRE1的机制诱导再生反应。基于 这些数据和其他数据我们的第二个实验目标是研究 TNFR2/IRE1信号转导及确定TNFR2激活的治疗效果是否依赖 在IRE1激活时。这些目标将在以下目标中得到检验： 具体目标1：研究tmTNF/TNFR2信号转导通路在改善脑功能中的性别特异性作用 运动功能和神经病理学。 A)我们将研究性激素在tmTNF/TNFR2信号通路中对运动改善的作用 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信号转导中在运动改善中的作用 雄性和雌性小鼠的功能和神经病理学。 特异性目的2：研究TNFR2诱导的雄性和雌性小鼠内源性修复机制。 A)我们将询问TNFR2诱导的内源性修复机制少突胶质细胞并确定 它们是女性运动恢复所必需的。 B)我们将询问TNFR2诱导的内源性修复机制神经元，并确定它们是否 在体内和体外，女性运动恢复所需的。