Targeting PARP Signaling as a Novel Treatment for Urologic Complications of Spinal Cord Injury
Abstract
Although survival rates have increased steadily over the past decades, spinal cord injury (SCI) still has a devastating impact on injured individuals, their caregivers, and their families. Active-duty military personnel are at significantly higher risk of SCI than individuals in the general population due to the risks associated with military training and service. The most visible effect of SCI is limb paralysis that may affect both lower and upper limbs to differing extents. Less obvious is the loss of bladder and bowel control, which can lead to psychological distress and a significantly diminished quality of life as a result of incontinence, increased likelihood of urinary tract infection, and elevated risk of damage to the kidneys. SCI is extremely costly to individuals, both financially and psychologically, and in spite of significant advancements in care of individuals with SCI, there is currently no cure. The relatively young age at which military personnel are likely to incur their spinal injury, as well as the increased likelihood of surviving their injuries means that such individuals and their families bear a lifelong health and financial burden from their condition. A significant proportion of the clinical expenditures for individuals with SCI is directly related to management of the bladder, and while current medications to improve bladder control provide some symptomatic relief, they are often associated with undesirable side effects and variable long-term efficacy. To explore new avenues for treatment of the urinary complications of SCI, our group has performed an in-depth analysis of the molecular signals that drive changes in the bladder in animal model of SCI. This analysis has identified a protein in cells called PARP-1 that is activated by SCI, in parallel with increases in deposition of collagen, a substance that increases stiffness of the bladder wall making it less flexible. Treatment of animals with SCI with inosine, a molecule known to inhibit PARP-1, led to reduced collagen deposition. Previous studies from our group showed that inosine could decrease overactivity of the bladder in animals with SCI. Together, these results suggest that PARP-1 may be responsible for signaling that leads to damaging complications of SCI. Based on our new data, we will investigate how PARP-1 leads to structural and functional changes in the bladder following SCI by determining how treatment of SCI animals with additional PARP inhibitors leads to changes in cells responsible for collagen production, and how they impact bladder function. Although the proposed studies will use an animal model of SCI, we believe the results of this research will be relevant to humans with spinal injury, since the mechanisms that regulate collagen production in the bladder are similar in both species. If successful, we anticipate results from our studies could lead to the use of PARP inhibitors in humans with SCI to diminish complications, since PARP inhibitors are already approved for use in diseases such as cancer. Studies such as ours that investigate the basic mechanisms that underlie the complications of SCI have the potential to uncover new strategies for treatment and to impact the health and quality of life of paralyzed military personnel and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310446
Entities
People
- Rosalyn M Adam
Organizations
- United States Army