# TNFR2 Sex Differences and EAE

> **NIH NIH R01** · DREXEL UNIVERSITY · 2022 · $378,750

## Abstract

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.

## Key facts

- **NIH application ID:** 10384115
- **Project number:** 1R01NS124123-01A1
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** John Roland Bethea
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $378,750
- **Award type:** 1
- **Project period:** 2021-12-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10384115

## Citation

> US National Institutes of Health, RePORTER application 10384115, TNFR2 Sex Differences and EAE (1R01NS124123-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10384115. Licensed CC0.

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