Muneer Laboratory
Laboratory of CNS Injury and Molecular Therapy
Ang II staining
ICAM-1 antagonistic peptide for TBI treatment
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we are targeting intercellular adhesion molecule 1 (ICAM-1) that has a significant role in the regulation of vascular permeability and neovascularization, and transmigration of leukocytes to the brain. Adhesion of leukocytes to endothelial cells is a critical step in the migration of leukocytes into injured tissues. This adhesion is regulated in part by interactions between ICAM-1 on endothelial cells and a group of glycoproteins such as leukocyte function-associated antigen (LFA-1) on leukocytes and macrophage-1 antigen (Mac-1) on neutrophils, monocytes, and macrophages. ICAM-1 is known to initiate neuroinflammatory response through the transmigration of leukocytes into the brain via cell adhesion protein- paxillin and focal adhesion pathways. These events finally lead to neuroinflammation, neurodegeneration, and cognitive and sensory-motor deficits. However, in TBI, the downstream mechanism of injury-induced transmigration of leukocytes to the brain remains elusive. Moreover, it is not clear whether blocking ICAM-1-mediated transmigration of leukocytes within the neurovascular unit provides better outcomes after TBI. Therefore, an approach to suppress ICAM-1 activity either genetically or pharmacologically could be a valuable therapeutic strategy for promoting recovery from TBI.
Therapeutic strategy for neurovascular remodeling in alcohol use disorder
Peptide-based therapeutic strategies have been pursued in various neuropathologies and disorders including alcohol abuse and CNS injury. Activation of endogenous antioxidant genes that normally combat oxidative damage using peptide activators is a specific and viable treatment strategy. Compared to chemical antioxidants, peptide treatments have few if any side effects and show high therapeutic efficacy in clinical trials. Thus, in the current project, we propose to improve Nrf2 activity using a synthetic NP (EMD Millipore, Billerica, MA). NP is a 14mer peptide conjugated to a cell-penetrating trans-activating transcriptional activator (TAT) sequence at the C-terminus that targets the Nrf2 binding site on Keap1. The peptide disrupts Nrf2-Keap1 interaction and stabilizes cytosolic Nrf2 and promoting its nuclear translocation and interaction with ARE.
Nrf2 signaling as a therapeutic target against TBI
The Nrf2 transcriptional system is an endogenous defense mechanism present within cells. Since Nrf2 boosts the expression of many detoxifying, cytoprotective, and anti-inflammatory genes by interacting with the antioxidant response element (ARE) in their regulatory regions, it has the potential to be a novel and clinically relevant therapeutic target for TBI. In this project, we explore this potential by activating Nrf2, thereby promoting antioxidant and detoxifying genes in mild stretch injury-induced TBI in vitro. In addition, injured animals treated with Nrf2 Activator III peptide activates the Nrf2 transcriptional system, and we analyzed its effect on TBI associated neurovascular and neurological impairments. TBI will be achieved in animals using the standard lateral fluid percussion injury (FPI) method in vivo, and in cells by inflicting injury to human brain microvascular endothelial cells (hBMVEC) in vitro. Using Nrf2 knock-out mice, we demonstrate the neuroprotective roles of Nrf2 as antioxidant/anti-inflammatory agent against TBI.
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DRG neuron
Gene therapy for spinal cord injury
The long-term disabilities associated with spinal cord injury (SCI) are primarily due to the absence of robust neuronal regeneration and functional plasticity. The inability of axons to regenerate after SCI is attributable to a combination of effects including the non-permissive extrinsic central nervous system (CNS) environment and withdrawal of the intrinsic regenerative abilities present during development. Thus intrinsic mechanisms are important in promoting axonal regeneration after SCI. Moreover, the factor(s) that may be triggered to promote the initiation of a molecular growth program and axonal sprouting in SCI are largely unknown. In vivo gene delivery to sites of SCI has been useful for identifying patterns of axonal sensitivity to growth factors in the context of both acute and chronic SCI. However, only a few studies have been conducted to test this therapeutic strategy by gene delivery via viral vectors in animal models of SCI in vivo. Recently, we have developed a strategy of gene therapy by transferring Mst3b or GDF10 gene via AAV and assess its efficacy in enhancing axonal regeneration and functional recovery after SCI.
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Synergistic effect of TBI & alcohol and Post-traumatic stress disorder (PTSD)
Posttraumatic stress disorder (PTSD) is a mental health problem that some people develop after experiencing or witnessing a life-threatening event, like combat, a natural disaster, a road accident, or sexual assault. Here, in this proposal, we hypothesize that the traumatic brain injury (TBI)-induced various mental illness such as anxiety, depression, sleep disturbances, heightened stress and pain sensitivity, and impulse control deficits are often correlated with intensified alcohol use that leads to PTSD or exacerbates the PTSD. In this project, we study the leading causes of PTSD in the synergistic effect of TBI and alcohol.
