a). Efficacy and Safety of an Iron Chelator Therapy for TBI-induced Chronic Disabilities in a Rodent Model (Funded by VA R&D Merit Review Grant mechanism; PI: Bose). This VA funded Merit Award studies will test the preclinical evaluation of the safety and efficacy of a hexadentate iron chelator to remove microbleed-induced iron, a powerful catalyst of inflammation, and to upregulate neural and vascular trophic agents to protect and heal injured neural and vascular tissues. These studies will increase our understanding of microbleed (iron)-induced inflammation and the potential therapeutic benefits provided by an iron chelating drug to address three long-term hallmark TBI disabilities (e.g. motor, cognitive and anxiety) that significantly impact the quality of life.
b). Biofluid-based Biomarker and MRI-based Neuroimaging Assessments as Translational Pathophysiological Outcome Measures in TBI. The primary objective of this research work (NIH funded; Co-I: Bose; PI: Wang) is to determine essential biofluid and MRI-based biomarkers representing the major TBI pathophysiological mechanistic subphenotypes. These data will be cross-validated across multiple TBI models and research sites. The central hypothesis is that in preclinical multi-model multi-site TBI animal model setting, quantitative MRI-based neuroimaging biomarker and biofluid-based biomarker assessment are useful pathophysiological outcome measures that can help to address a range of clinical TBI pathophysiological mechanistic subphenotypes including axonal injury, loss of synaptic continuity, white matter integrity, microvascular injury, neuroinflammation and manifestation into chronic neurodegernative condition. Bose lab has been conducting the research related to closed head TBI model for this multi-model multi-site TBI studies.
c). Preservation of spinal cord tissue resulting from Ischemia following Aortic Surgery (PRESERVE: PIs: Bose and Spiess): This research initiative will create a clinically relevant rodent model (unique UF model) of spinal cord ischemia which most closely approximates the clinical situation that happens following extensive thoracoabdominal aortic surgeries. More importantly, once the model is validated, we will test the efficacy and safety of a newer and more effective perfluorocarbon O2 therapy in this rodent model of spinal cord ischemia. Current therapies do not directly enhance oxygen delivery to the ischemic spinal cord in-theater, and cannot be used early enough to reduce neurological damage. Thus, creation of a clinically relevant rodent model and testing of a novel oxygen release therapeutic are critical. Spinal cord ischemia is of great interest in the fields of cardiovascular and vascular surgery leading to neurology and rehabilitation medicine. Reliable and reproducible experimental model is crucial for both basic scientists and surgeons to understand the pathophysiology and to develop clinical therapeutic strategies effectively.
d). Therapeutic impact of an iron-chelating agent on long-term motor disabilities in an animal model of Parkinson’s disease (PD) (Pilot work, PI: Bose). The objective of this pilot preclinical work is to evaluate the therapeutic impact of a new iron-chelating agent on long-term motor disabilities in 6-hydroxydopamine (6-HDA) toxin-induced rodent model of Parkinson’s disease. There is increasing evidence that iron is involved in the mechanisms that underlie many neurodegenerative diseases, including PD. It is proposed that the high basal iron content, with the vulnerability to accumulate iron with age and in disease, makes Substantia nigra (SNc) region susceptible to PD neurodegeneration. High concentrations of reactive iron can increase oxidative-stress, neuronal vulnerability and neurodegeneration.
e). Transcranial magnetic stimulation (TMS) for the treatment of repetitive blast and acceleration deceleration impact Traumatic brain injury-induced post-traumatic epilepsy (Pilot work, PI: Bose). The goal of this pilot project is to examine the molecular mechanisms associated with repetitive closed head and blast TBIs-induced post-traumatic epilepsy (PTE). The objective is to test the hypothesis that repetitive TBIs are associated with the development of PTE, and a non-invasive repetitive transmagnetic stimulation (rTMS) therapy will attenuate the development of PTE in a rodent model of TBI.
f). Treatment efficacy of transcutaneous auricular branch vagal nerve stimulation (tcabVNS) for hallmark TBI disabilities. Traumatic brain injury (TBI) induces enduring disabilities in cognition, balance, and motor control (including spasticity). Although the specific mechanism of these disabilities is unknown, our studies have shown that TBI induces significant cell loss in the primary noradrenergic (NA) nucleus locus coeruleus (LC). Our previous studies showed that TBI induces a decrease in NA expression in multiple functional neuro-substrates for cognitive, balance, and motor control areas and these decreases in NA expressions were correlated with cognitive impairment, balance disability, and spasticity. Thus, this pilot study is to provide new knowledge regarding tcabVNS as a non-invasive alternative means to therapeutically upregulate NA function in the setting of TBI.
g). Development and refinement of two clinically relevant rodent stroke models. The objective of this initiative is to create two clinically relevant rodent stroke models (e.g. white matter stroke model, and a hemorrhagic stroke model) to provide a quantitative and comprehensive evaluation of the development of hallmark stroke disabilities (e.g. motor and vestibulomotor) and to test potential preclinical therapies.Research on human neurorehabilitation following stroke is one of major initiatives of the Brain Rehabilitation Research Center (BRRC). Compared to traumatic brain injury (TBI) the availability of preclinical medically relevant stroke research models to provide the opportunity for preclinical therapy development and testing is greatly undeveloped. Thus, to complement stroke related clinical rehabilitation research, there is a requirement for creation of clinically relevant stroke models (e.g. ischemic and hemorrhagic) to provide human stroke related disabilities in an animal model to test clinical questions that cannot be tested in stroke patients. The potential for a preclinical medically relevant stroke model is to provide a platform for discovery of paradigm shifting leaps in the neurobiology of injury and rehabilitation to guide and accelerate the BRRC’s translational research mission.
h). A Non-Pharmacological Intervention to Mitigate Chronic Pain Following TBI in a Rodent Model (Pilot work; PI: Bose). These studies are designed to provide a mechanism-driven neurobiological basis for TBI- and electro-acupuncture (EA) therapy-induced changes in pain/headache behavior that manifest as facial and somatic hyperalgesia/allodynia. We propose that EA based selective neurostimulation induces a robust upregulation of monoamines and GABA-argic neuromodulation that significantly reduces pain/headache by normalizing neuronal excitability, reducing neuro-inflammation and vascular dilatation in the trigeminosomatic and trigeminovascular pain/headache pathways.
i). Brain Rehabilitation Research Center (BRRC; Co-PI: Bose; PI: Bauer). This is an US Department of Veterans Affair RR&D funded national center, where Dr. Bose is the Associate Director. The BRRC funds the infrastructure and coordinating staff to enhance the research of 4 Research Initiatives including Rehabilitation Neuroscience. The BRRC enhances the research programs of 28 Center investigators and their respective research teams by providing sophisticated technological Core Services, state-of-the-art measurement and analysis of brain function and motor performance core laboratories, and administrative organization and support of research activity. This Center model forms a technological and administrative resource platform which empowers BRRC investigators to more efficiently conduct collaborative thematically cohesive research. The Brain Rehabilitation Research Center is dedicated to innovation and refinement of treatments to potentiate neural plasticity and neural network reorganization that substantially improve motor, cognitive and affective functions affected by neurologic disease or injury.