Targeting Angiotensin-Based Neuroimmune Cross Talk for Treatment of Neuromuscular Trauma
Abstract
FY19 Restore Focus Areas: (1) Pain management strategies following acute and/or chronic neuromusculoskeletal injury that are fast-acting, long-lasting, and free of adverse side effects and (2) solutions to accelerate recovery and restore Warfighter performance in training and operational environments. Research Level 1: New ideas that represent innovative approaches and have the potential to make an important contribution within the RESTORE Focus Areas. Background: In recent armed conflicts, traumatic soft tissue and peripheral nerve injuries have accounted for more than half of military casualties. Major complications of muscle and nerve injuries include neuropathic pain and impaired muscle function, which can lead to significant disability and loss of quality of life. These kinds of injuries pose a threat to overall health and readiness. Inflammatory processes that fail to resolve are a root cause of these impairments, which current therapies do not address adequately. For example, current pain relief options are effective in as few as one in four neuropathy patients, and non-steroidal anti-inflammatory drugs have potentially severe side-effects. An additional challenge is that current therapies do not necessarily support nerve repair, which is critical to reduce pain, restore normal sensation and muscle function, and promote resolution of inflammation. In summary, poorly managed neuropathy and chronic muscle inflammation represent significant unmet military healthcare problems that currently lack comprehensive strategies to address deficiencies. Rationale: Recent research has made the surprising discovery that a peptide hormone, angiotensin II (Ang II), previously recognized for its role in controlling blood pressure, is an important mediator of symptoms similar to those found in neuromuscular injury patients. Blocking the effects of Ang II is protective to nerves and anti-inflammatory. Ang II production from injured nerves is associated with nearby accumulation of white blood cells (macrophages and T-cells). Our prior and ongoing work confirms that inhibiting Ang II receptor signaling in these white blood cells can reduce pain in rodent models of nerve injury. Other studies suggest that Ang II may also be a key player in muscle scarring after injury. Remodeling of the injured muscle compromises healing and impairs function. Based on these findings, we conclude that Ang II signaling pathways are critically important for the development of pain, neuropathy, non-resolving inflammation, and scarring in muscle, which contribute to suboptimal healing of muscle and impaired function. Our overall goal is to develop the underlying knowledge to enable us to demonstrate the translational feasibility and efficacy of targeting Ang II signaling. We hypothesize that an Ang II receptor-blocking drug that is free of blood pressure-related side effects will achieve optimal, sustained inhibition of the effects of Ang II. Such specific inhibition of Ang II signaling will reduce the excitability of injured nerve fibers and promote their regeneration while fostering resolution of inflammation and reduced scarring in damaged muscles, allowing for nontoxic, long-term mitigation of symptoms of neuromuscular injury. The inhibition of Ang II signaling will be evaluated in our laboratories in established mouse and rat models of traumatic nerve and muscle injury. Specific Aims: Aim 1. Determine the interaction between nerve and muscle injury in mice. Aim 2. Establish the anti-inflammatory and pain-relieving effects of inhibiting Ang II signaling in mice. Aim 3. Determine a dosing regimen of Ang II signaling inhibitors to reduce inflammation and spare/improve muscle function in rats. Study Design: Inhibition of non-blood pressure-related Ang II signaling will be both anti-inflammatory and analgesic in injured muscle and nerve. We hypothesize that this dual targeting approach will relieve pain and infl
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110197
Entities
People
- Andrew J Shepherd
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army