Muneer Laboratory
Laboratory of CNS Injury and Molecular Therapy
Department of Biomedical Engineering
Our projects
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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.
Muneer Lab work published as a cover image in the Journal of Neuroscience.
Expression of NET marker H3Cit (red) colocalized with CD13 (green, microvessel), and DAPI (blue, nucleus) in the brain microvessel of injured mouse.
Peptide therapeutic study for blocking the formation of neutrophil extracellular traps (NET) in TBI
Adhesion of leukocytes to endothelial cells is a critical step in the migration of leukocytes into injured tissues. Previously, it has been demonstrated that activation of leukocytes, especially neutrophils cause the release of nuclear and granular contents to form an extensive web-like structure of DNA called neutrophil extracellular traps (NET). However, in TBI, the mechanism of injury-induced formation of NET and its mechanistic regulatory role in thrombosis remains elusive. Moreover, it is not clear whether blocking of formation of NET provides better outcomes after TBI. Therefore, an approach to suppress the formation of NET would be a valuable therapeutic strategy and to analyze the efficacy of the therapy in the functional recovery level after TBI. Here, we hypothesize that inhibition of peptidyl arginine deiminase type 4 (PAD4), an enzyme required for NET formation, using PAD4 antagonistic peptide (PAP) will attenuate the formation of NET, NET-induced thrombosis, and promote neovascularization and functional recovery after TBI.
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PCR amplification and CRISPR cleavage analysis using ICAM-1 primer after treating with ICAM-1 CRISPR/Cas9 AAV. Journal of Neuroscience, e1742232024.
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.
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.
