# Soluble TNFa in the development of autonomic dysreflexia after spinal cord injury

> **NIH NIH R01** · DREXEL UNIVERSITY · 2020 · $570,901

## Abstract

PROJECT SUMMARY
 Cardiovascular disease and susceptibility to infection are two leading causes of morbidity and mortality
for individuals with spinal cord injury (SCI). One of the major contributors to SCI-associated cardiovascular
disease and immune deficiency is the syndrome autonomic dysreflexia (AD), an amplified reaction of the
autonomic nervous system in response to sensory stimuli below the injury that manifests in 70%-90% of people
who have sustained a high SCI. AD is hallmarked by extreme, sudden bouts of hypertension and reflexive
bradycardia (i.e. heart rate decrease). Over time, AD events become more severe. These chronic, frequent
episodes of hypertension are thought to lead to peripheral vascular dysfunction and immune suppression that
contribute to cardiovascular disease and susceptibility to infection, respectively. Merely limiting AD intensity
may have significant therapeutic value and improve SCI patients' overall health. The gradual exacerbation of AD
is thought to be driven by plasticity of circuits below the lesion that results in an exaggerated spinal sympathetic
reflex. Unfortunately, the mechanisms that trigger this maladaptive plasticity are still poorly understood,
limiting the development of prophylactic treatments. Interestingly, an activated neuroimmune system is thought
to be an underlying factor in aberrant plasticity and hyperexcitable circuits correlated with other pathologies.
The pro-inflammatory, soluble form of the cytokine tumor necrosis factor α (sTNFα) has been implicated in
initiating inflammation in many contexts. Furthermore, sTNFα is associated with various forms of plasticity that
could increase neuronal excitability. We hypothesize that sTNFα in spinal cord below a SCI plays a crucial role
in triggering aberrant plasticity that leads to hyperactivity of the spinal sympathetic circuit after SCI and the
secondary, intensification phase of AD. Moreover, this proposal will focus on the hypothesis that sTNFa/TNFR1
signaling in neurons involved in the circuit is central to the exacerbation. We will test our hypotheses using an
established adult rodent spinal cord thoracic level 3 transection model that reliably results in AD. The overall
goals of this multi-PI proposal are to: 1) further interrogate the therapeutic potential of inhibiting sTNFα to
reduce AD (Aim 1); 2) investigate the mechanisms underlying how neuronal sTNFα/TNFR1 mediates AD (Aims
2 and 3).

## Key facts

- **NIH application ID:** 9902562
- **Project number:** 5R01NS106908-03
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** John Roland Bethea
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $570,901
- **Award type:** 5
- **Project period:** 2018-04-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9902562

## Citation

> US National Institutes of Health, RePORTER application 9902562, Soluble TNFa in the development of autonomic dysreflexia after spinal cord injury (5R01NS106908-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9902562. Licensed CC0.

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