The Role of Osr1 in Bladder Dysfunction from Spinal Cord Injury
Abstract
Research Objective: The overarching objective of this research proposal is to explore a new method of treating bladder disease following spinal cord injury. Proposal Rationale: Active military personnel are at higher risk than the general population of incurring spinal cord injuries, especially from explosions and gunshot wounds. These severe injuries disrupt bladder control by damaging the nerves that cause the bladder muscles to contract. This disruption results in bladder contractions that are out of sync with the opening of the urethra (where the urine exits the bladder), resulting in a bladder that is unable to properly drain. Although the bladder tries to compensate for this disruption by contracting more and more vigorously, these powerful contractions cause certain cells in the bladder to secrete scar-tissue products that make the bladder become stiff and rigid. Despite knowing that an accumulation of scar-tissue products causes bladder stiffness following spinal cord injury, we do not know how this process occurs. Ultimately, this sequence of events culminates in a bladder that is unable to store or empty urine. When this occurs, the only treatment to preserve the bladder and reduce urine accidents is to insert a plastic tube (i.e., catheter) into the bladder. Although this treatment is an effective means of emptying the bladder, it puts patients at an increased risk of contracting urinary tract infections, and it significantly impairs their quality of life and their self-esteem. This illustrates the need for a novel treatment to circumvent the use of catherization and prevent the bladder from becoming stiff following spinal cord injury. We propose that a gene called Odd-skipped related (Osr)1 functions to regulate the stiffness of the bladder following spinal cord injury. This speculation arose during studies in our laboratory where we discovered that newborn mice lacking the Osr1 gene have a floppy bladder that never gets stiff. We became even more intrigued by this finding when we discovered that several mouse embryos lacking the Osr1 gene did not even have a bladder! These findings led us to consider that Osr1 may function as a master gene that controls the formation of the bladder and the bladder’s ability to stiffen after spinal cord injury. In further support of this idea, we found that mice with spinal cord injuries have high levels of the Osr1 gene and a rigid bladder. Thus, we are seeking to discover if and how the Osr1 gene causes the accumulation of scar-tissue products in the bladder following spinal cord injury in mice (Aim 1). Using our preclinical model of bladder disease, we will also assess the effect of two drugs (nintedanib and pirfenidone), which are currently used to treat a form of lung disease caused by a similar accumulation of scar-tissue products in the lungs (pulmonary fibrosis). We will determine if these two drugs reduce bladder stiffness and Osr1 gene expression in mice with spinal cord injury (Aim 2). Ultimate Applicability and Impact: Although bladder disease in military personnel is extremely debilitating and significantly impairs independent living, there are no effective treatment options to preserve the bladder and/or treat bladder disease caused by spinal cord injury. In the short term, successful completion of our proposal will advance the field of spinal cord injury research by demonstrating if and how targeting the deposition of scar-tissue products (through the Osr1 gene and drugs used to treat pulmonary fibrosis) can reduce bladder stiffness and increase bladder capacity. Long term, these findings could lay the foundation upon which Osr1-inhibitors, nintedanib or pirfenidone, would be used to treat bladder disease in patients with spinal cord injury in lieu of a bladder catheter. While our proposed proof-of-concept studies will be conducted in preclinical models of bladder disease, our translational findings could ultimately benefit all patients with bladder di
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110899
Entities
People
- Indra Gupta
Organizations
- McGill University Health Centre
- United States Army