TNFR2 Sex Differences and EAE

TNFR2 性别差异和 EAE

• 批准号: 10532717
• 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 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532717
• 关键词: ATF6 gene; Agonist; Cell Death; Cells; Central Nervous System; 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; Motor; Multiple Sclerosis; Mus; Myelin; Natural regeneration; Nerve Degeneration; Neuroimmune; Neuroimmune system; Neurologic; Neurons; Oligodendroglia; Pathology; Pathway interactions; Physiological; Predisposition; Process; Protein Biosynthesis; Proteins; Publishing; Quality Control; Receptors, Tumor Necrosis Factor, Type II; Recovery of Function; Regenerative response; Role; Series; Sex Bias; Sex Chromosomes; Sex Differences; Signal Induction; Signal Transduction; Stress; TNFRSF1B gene; Testing; Therapeutic; Therapeutic Effect; Work; XBP1 gene; burden of illness; hormonal signals; improved; in vivo; male; motor disorder; motor function improvement; motor impairment; motor recovery; neuroinflammation; neuropathology; novel; painful neuropathy; pharmacologic; 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（MS）的易感性被认为部分是由于神经炎症 和与神经退化有关的疾病负担。众所周知，女性有更强大的 然而，与男性相比， 男性。因此，在MS的背景下，这提出了一个有趣的问题。女性，由于拥有一个 更强的炎症反应，具有内源性保护/修复机制，以保护 中枢神经系统（CNS）炎症诱导的病理，男性没有或 对男性没有效果吗该提案基于广泛的初步和已发布的数据 这表明女性而非男性中的tmTNF/TNFR 2信号传导显著改善了运动功能， 通过激活神经元中的内源性修复程序， 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 tmTNF/TNFR 2的差异诱导运动功能和神经病理学的改善。我们还 具有非常新颖的药理学和遗传学数据， 少突胶质细胞通过IRE 1依赖性机制诱导再生反应。基于 我们的第二个实验目标是研究这些数据和其他数据之间的交叉点， TNFR 2/IRE 1信号传导，并确定TNFR 2激活的治疗作用是否依赖于 在IRE 1激活后。这些目标将在以下目标中得到检验： 具体目的1：研究tmTNF/TNFR 2信号传导在改善肿瘤细胞增殖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/TNFR 2信号传导中在改善运动神经功能中的作用。 功能和神经病理学。 B）我们将研究性染色体在tmTNF/TNFR 2信号转导中在改善运动神经功能中的作用。 功能和神经病理学。 具体目的2：研究TNFR 2诱导的雄性和雌性小鼠内源性修复机制。 A）我们将询问TNFR 2诱导的内源性修复机制少突胶质细胞，并确定是否 它们是女性运动恢复所必需的。 B）我们将询问TNFR 2诱导的内源性修复机制神经元，并确定它们是否是内源性修复机制神经元。 在雌性动物体内和体外运动恢复所需的。