Improving Bladder Compliance and Function After Spinal Cord Injury by Targeting Aberrant Matrix Metalloproteinase-Dependent Remodeling of the Bladder Wall
Abstract
Background/Readiness: Spinal cord injury (SCI) results in the loss of coordinated bladder function and detrusor sphincter dyssynergia. While these debilitating consequences have been well recognized in the research field, few, if any, studies have considered the loss of bladder compliance, resulting from abnormal remodeling that alters its viscoelastic properties. From a clinical perspective, low compliance results in urine retention with increased risk of urinary tract infections, pyelonephritis, and vesico-ureteral reflux, a condition that is associated with hydronephrosis and ultimately renal failure. Moreover, the frequency of bladder care is based, in part, on bladder compliance; low compliance dictates more frequent catheterizations- a feature that impacts quality of life. The proposed studies address a translational pathway, targeting bladder compliance, that would reduce medical complications and offer greater flexibility in day-to-day bladder care. We propose to improve bladder compliance and function after SCI through blockade of matrix metalloproteinases (MMPs), proteases that are well known for their ability to remodel the extracellular matrix, support aberrant cell division/migration, and contribute to hypertrophy. Our published and preliminary data, based upon a clinical trial in dogs and further validated in mice, collectively confirm the remarkable involvement of MMPs in remodeling of the bladder wall within the first several days after SCI through a mechanism that involves an ERK-dependent signaling cascade that promotes hyperplasia in the bladder wall. Importantly, pharmacological blockade of MMPs, during this acute phase, results in improved long-term bladder compliance in both spinal cord injured dogs and mice. The proposed studies, which build upon the above findings, will examine the extent to which MMPs direct abnormal remodeling in the subacute (7 days) and chronic phases (14 and 21 days) after SCI. We will determine if blockade during these sensitive periods, as the bladder progresses from a flaccid to a dyssynergic state, will reduce aberrant remodeling and improve long-term bladder compliance/function. Hypothesis: We hypothesize that neurogenic bladder dysfunction results in prolonged exposure to MMP- directed aberrant remodeling of the bladder wall and temporally defined, transient blockade of this proteolytic activity will arrest this pathologic process and improve long-term bladder function and compliance. Study Design Aim 1: To identify those MMPs that are upregulated in the bladder after SCI and if their profile changes as the bladder progresses from a flaccid to a dyssynergic state, we will define the time course and magnitude of upregulation of MMPs in the bladder wall 7 days to 6 weeks post injury. Gelatin and reverse zymography and rtPCR will be used to assess the activity/expression of MMPs and their tissue inhibitors of MMPs. Aim 2: To define the contribution of MMPs to progressive remodeling of the bladder wall in the subacute and chronic phases after SCI, we will examine bladder hypertrophy and altered viscoelastic properties at 6 weeks post injury after short-term systemic (subcutaneous) or local (via a urethral catheter) delivery of the general inhibitor of MMPs, GM6001, or a specific MMP inhibitor, ND-33-6, at subacute (7 days) and chronic (14 and 21days) time points post injury. Aim 3: To determine if MMP inhibition will improve bladder compliance and function after SCI, we will assess efficacy of MMP inhibition at 42 days post injury. During recovery, neurological function will be monitored weekly. Prior to euthanasia, bladder function will be evaluated in vehicle and drug-treated animals by awake cystometry. The bladder and spinal cord will then be removed for analyses of bladder hypertrophy and viscoelastic properties as well as white matter sparing and lesion volume in the injured spinal cord. Controls for each of these aims include surgical
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210645
Entities
People
- Linda Noble-Haeusslein
Organizations
- United States Army
- University of Texas at Austin