# Center for Restoration of Nervous System Function

> **NIH VA I50** · VA CONNECTICUT HEALTHCARE SYSTEM · 2020 · —

## Abstract

Rehabilitation, as well as quality of life, in Veterans with nerve and spinal cord injury, traumatic limb amputation,
burn injury, and peripheral neuropathy is severely hampered by chronic pain and spasticity. Current treatments
in many cases are ineffective or partially effective, and can be addictive. Our Center has developed robust
research programs with unique capabilities to develop novel, more effective, and non-addictive treatments for
Veterans with chronic pain and spasticity. Our research has progressed from molecular physiological studies in
vitro and in animal models, to stem cell-derived models such as iPSCs and clinical translational studies, and
from rare human familial disorders that provide genetic models to more common disorders that affect broader
populations. We will now build on this progress in the five major research programs summarized below.
Research Program I: Nav1.7—From Target to Therapy for Pain. We have provided a direct link between
Nav1.7 and human pain disorders, and collaborated with Pfizer and Biogen to advance clinical studies of
orally-bioavailable, Nav1.7-selective blockers for the treatment of neuropathic pain. As a parallel route to new
pain medications, we will also move forward with a large-scale in-house effort to identify the atomic structure of
human Nav1.7 and the molecular determinants of the dual Nav1.7 blocking/gating modifying action of
carbamazepine, which should provide a high-resolution scaffold for rational drug design.
Research Program II: Molecular Genetics of Pain Resilience. We are a worldwide hub for molecular
genetic studies on IEM, a genetic model of human neuropathic pain, in which gain-of-function mutations of
Nav1.7 produce profound hyperexcitability of peripheral pain-signaling DRG neurons that cause pain. We now
plan in-depth study of a family with the Nav1.7-S241T mutation that causes IEM, whose individual members
each manifest pain with distinctly different severity, using an innovative platform of iPSC-derived sensory
neurons, and next-generation sequencing to identify and validate allelic variants that confer pain resilience.
Research Program III: Additional Targets for Pain Pharmacotherapy. Our studies have identified and
validated Nav1.8 and Nav1.9 as additional targets for pain in humans, and have expanded the spectrum of
human neuropathic pain disorders associated with mutations in Na+ channels. We will extend our findings of a
dual action of CBZ as a Na+ channel blocker/gating modifier, from Nav1.7 to Nav1.8 to establish the
generalizability of this novel concept. We will build a proteomics platform to identify channel partners that
regulate trafficking of Nav1.9 within nociceptors, which will advance us toward screening platforms and
enhance understanding of this channel, which has been implicated in both somatic and visceral pain.
Research Program IV: Neuroprotective Strategies in Sodium-Channel Related Peripheral
Neuropathies. We have started to unravel the cellular path...

## Key facts

- **NIH application ID:** 9757618
- **Project number:** 5I50RX002999-02
- **Recipient organization:** VA CONNECTICUT HEALTHCARE SYSTEM
- **Principal Investigator:** Sulayman D Dib-Hajj
- **Activity code:** I50 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9757618

## Citation

> US National Institutes of Health, RePORTER application 9757618, Center for Restoration of Nervous System Function (5I50RX002999-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9757618. Licensed CC0.

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