An Effective Strategy to Promote Axon Regeneration and Functional Recovery After Spinal Cord Injury
Abstract
Spinal cord injuries (SCI) cause devastating paralysis, loss of sensation below the level of the injury, and deficits of various autonomic functions, including bowel, bladder, and sexual functions. People who suffer from SCI usually lose the ability to walk and other essential abilities to live independently. Loss of bladder function greatly increases the risks of urinary tract infections, and SCI frequently causes other major long-term health risks, such as deep vein thrombosis, bone fractures, pressure sores, and autonomic dysreflexia, all of which are life-threatening. Currently, treatments to reverse paralysis and return other lost functions are not available, and people who have suffered SCI are permanently disabled. It has long been recognized that the greatest hope for functional recovery is to regenerate nerve fibers and restore their connections that are damaged by SCI. It is extremely challenging to achieve robust regeneration in the central nervous system (CNS) and to regain lost functions in adult mammals. However, in the past decades, researchers have made numerous breakthrough discoveries to regenerate damaged nerve fibers by targeting different genes and signaling pathways, including phosphatase and tensin homolog and some transcription factors for controlling neuronal growth. However, none of these approaches have been translated to clinics yet, and there is a persistent need to identify better targets and improved therapeutic methods. The best gene targets are probably those with the potential to impact multiple genes simultaneously. Among them, the transcriptional factor ZNF362 appears very important for controlling age-dependent decline in nerve regeneration in mammals. This project targets ZNF362, a critical signaling regulator downstream of the let-7 miRNA. We have recently shown that Let-7-associated genes are critical for regulating neural cell growth in adult mammals. Among them, ZNF362 plays an important role in controlling the growth failure of mature nerve cells after CNS injury. We plan to study the potential essential role of ZNF362 in controlling the age-dependent loss of nerve growth capacity in adult CNS and stimulate robust nerve regeneration and functional recovery after SCI by inhibiting ZNF362. We designed the small sequence-targeting peptide drugs that block ZNF362 function selectively. Our pilot studies demonstrated that treatments with our novel peptides against ZNF362 promoted robust regrowth of motor and sensory CNS nerves in adult rodents. We thus propose to evaluate the efficacy of our novel peptide drugs in promoting nerve regeneration and functional recovery after SCI using adult rat models. Aim 1: We will determine whether four ZNF362 antagonist peptides promote in vivo nerve regrowth and functional recovery in adult rats with transection SCI, aiming to select the top two optimal peptides. We have verified the high effectiveness of these four peptides in promoting nerve growth in vitro. Aim 2: We will validate the efficiency of the top two optimal ZNF362 peptides in promoting robust regrowth of motor nerve tracts and locomotor recovery in adult rats with contusion SCI, a translational model mimicking the lesions of most SCI patients. We have shown that transgenic ZNF362 deletion promotes robust CNS nerve regeneration in adult mice and that our ZNF362 peptides are highly effective for promoting nerve regrowth in vitro and in vivo. We anticipate that our novel peptide drugs will significantly advance our ability to treat SCI in adult mammals. Impact: Our proposed studies using contusion SCI and delayed drug delivery have the potential to lead to important new treatments for SCI patients. The results from our initial preclinical experiments with acute and subacute injuries should apply to the great numbers of individuals who suffer significant SCI every year. If our peptides are successful with contusion SCI, we plan to move this work to a peptide
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310611
Entities
People
- Shuxin Li
Organizations
- Temple University
- United States Army