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 study 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 of an iron-chelating drug to address three long-term hallmarks of TBI disabilities (e.g., motor, cognitive, and anxiety) significantly impact the quality of life.
b). Preclinical evaluation of an ER and field-ready therapy for spinal cord injury (funded by DoD; PI: Bose). Acceleration/deceleration and contusion spinal cord injury (SCI) cause micro-vessel shear injury, blood spinal cord barrier (BSCB) dysfunction, and hemorrhage. Iron deposited by diffuse micro-hemorrhage fuels inflammation through reactive oxygen species (ROS) and multiple inflammatory pathways, which further induce progressive disabilities. Cervical SCI (C-SCI) is a common and frequently devastating battlefield injury that can result in a broad range of life-long locomotor and spasticity disabilities. With advances in early evacuation and aggressive medical therapy, there are still no effective therapeutics that salvage spinal cord (SC) neurons/reduce progressive secondary damage. This DoD-funded study tests the acute preclinical evaluation of the efficacy and safety of an iron chelator to remove bleed-induced free toxic iron, a powerful catalyst of inflammation, and to upregulate neural and vascular trophic agents to protect and heal injured neural and vascular tissues. Mechanisms underlying iron-toxicity and treatment effects of iron chelator will be studied using a combination of histological, immunohistochemical, track tracing, and molecular biology-based assays to evaluate tissue bleed iron, oxidative stress, inflammation, markers for BSCB integrity, neural pathways, and neural and vascular protective factors.
c). Preclinical evaluation of efficacy and safety of a new iron chelator therapy in chronic spinal cord injury (Funded by VA R&D Merit Review Grant mechanism; PI: Bose). This VA R&D funded Merit Review grant is testing the preclinical evaluation of the safety and efficacy of a new iron chelator with or without a programmed locomotor therapy using our patented rodent bicycle in a chronic rodent model of contusion cervical spinal cord injury. The combination of two complementary therapies aims to amplify the robustness necessary to significantly improve function in a chronic setting of SCI significantly. This iron chelator will remove bleed-induced free toxic iron, a powerful catalyst of oxidative stress/inflammation, and with locomotor therapy, it will upregulate neural and vascular trophic agents to protect and heal injured neural and vascular tissues.
d). Brain Rehabilitation Research Center (BRRC; PI: Bose). This is a US Department of Veterans Affairs RR&D-funded national center, where Dr. Bose is the Interim 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 that empowers BRRC investigators to conduct collaborative, thematically cohesive research more efficiently. The Brain Rehabilitation Research Center is dedicated to the innovation and refinement of treatments to potentiate neural plasticity and neural network reorganization that substantially improve motor, cognitive, and affective functions affected by neurologic injury or diseases.
e). A Non-Pharmacological Intervention to Mitigate Chronic Pain Following TBI in a Rodent Model (Co-I: Bose; PI: Hou; funded by Department of Veterans Affairs). These studies are designed to provide a mechanism-driven neurobiological basis for TBI- and electro-acupuncture (EA) therapy-induced pain/headache behavior changes 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.
f). Feasibility of Using PET Imaging for Detection of Treatment-Induced Changes in Chronic Neuroinflammation Following TBI (Co-I; PI: Floyd Thompson; funded by Department of Veterans Affairs). The purpose of this study is to test the feasibility of developing a preclinical platform for the study of TBI-induced chronic neuroinflammation using PET imaging for the detection and surveillance of inflammation. In addition, these studies will test the putative efficacy of pharmacologic treatment (methylphenidate) to upregulate central noradrenergic and dopaminergic innervation. This proposal addresses a clinical problem, (chronic neuroinflammation) that is known to be a major factor in secondary brain injury and the worsening of TBI-induced disabilities.
g). Preclinical Application of Oxygen Therapeutic for Acute Spinal Cord Injury (Funded by DoD; PI: Bose). The work outlined in this pilot grant will test the preclinical evaluation of the safety and efficacy of novel patented IV emulsions of perfluorocarbon (PFC) nanoparticles, to limit the ischemic penumbra and improve motor disabilities following contusion cervical spinal cord injury.
h). Functionalized Enzyme Treatments for Dual-Targeting of Inflammation in Spinal Cord Injury Co-I (Co-I; PI: Christine Schmidt). In this project, indoleamine-2,3-dioxygenase (IDO) is proposed as a therapeutic option for dual-targeting classical inflammation and neuroinflammation processes, including glial scarring in SCI. Damage to the CNS results in a dynamic, complex sequela of neuroinflammation, glial reactivity, and cell death that ultimately hinders regeneration. More specifically, trauma can cause an autoimmune-type response in which infiltrating cells, or leukocytes, attempt to resolve damage at the lesion site (i.e., classical inflammation response). Classical inflammation can further initiate neuroinflammation involving resident glial cells like microglia and astrocytes. While necessary for repair, inflammation chronically exacerbates injury in the form of scarring and cellular degeneration. In this project, indoleamine-2,3-dioxygenase (IDO) is proposed as a therapeutic option for dual-targeting classical inflammation and neuroinflammation processes, including glial scarring in SCI. IDO is a tryptophan-catabolizing enzyme that is upregulated in response to pro-inflammatory cytokines as a feedback mechanism for monocytes, macrophages, T-cells, and other inflammation-associated cells.
i). 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 neurodegenerative condition. Bose lab has been conducting research on the closed-head TBI model for this multi-model multi-site TBI study.
j). Preservation of spinal cord tissue resulting from Ischemia following Aortic Surgery (PRESERVE: PI: Bose): 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, creating a clinically relevant rodent model and testing a novel oxygen-release therapeutic are critical. Spinal cord ischemia is of great interest in cardiovascular and vascular surgery, leading to neurology and rehabilitation medicine. A reliable and reproducible experimental model is crucial for basic scientists and surgeons to understand the pathophysiology and develop clinical therapeutic strategies effectively.
k). Oxygen Therapeutics for Spinal Cord Injury (PIs: Bose, Mitchell, and Fuller, Evelyn F. & William L. McKnight Foundation). The pilot grant will test the preclinical evaluation of the safety and efficacy of several innovative Oxygen therapies to limit the ischemic penumbra and improve motor and respiratory disabilities. The objective of this project is to gather sufficient data to support a PO1 project.
l). Development and refinement of two clinically relevant rodent stroke models. This initiative aims to create two clinically relevant rodent stroke models (e.g., a 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 the 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 the 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 discovering paradigm-shifting leaps in the neurobiology of injury and rehabilitation to guide and accelerate the BRRC’s translational research mission.
m). 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). This pilot preclinical work aims to evaluate the therapeutic impact of a new iron-chelating agent on long-term motor disabilities in a 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 the Substantia nigra (SNc) region susceptible to PD neurodegeneration. High concentrations of reactive iron can increase oxidative stress, neuronal vulnerability, and neurodegeneration.
n). 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). This pilot project aims 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.