Krishnan M. Dhandapani, Ph.D. - US grants

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a devastating neurological injury afflicting over 1 million people annually, including a large number of young adults and military personnel. Cerebral edema is associated with increased intracranial pressure (ICP) and a poor clinical outcome following TBI, although the cellular mechanisms underlying this process remain unknown. This gap in the understanding of cerebral edema formation contributes to the lack of clinically- effective therapeutics for TBI patients. Recent work by our laboratory demonstrates that acute neuronal necrosis stimulates the passive release of high mobility group box protein 1 (HMGB1), which in turn induces glial swelling and cerebral edema. Specific Aim 1 will establish whether activation of individual NMDA receptor subunits increase neuronal injury and cerebral edema following experimental TBI. The incorporation of NR2A and NR2B knockout mice will determine whether individual NR2 subunits contribute to HMGB1 release, brain swelling, and neurological outcome using following head trauma. Specific Aim 2 will determine whether toll-like receptor-4 (TLR4) mediates the pro- inflammatory and cerebral edema promoting effects of HMGB1. The ability of HMGB1 to stimulate the astrocytic water channel, AQP4, will also be addressed in TLR4 mutant mice. Specific Aim 3 will determine whether HMGB1 may represent a novel biomarker to predict the development of cerebral edema following head trauma in humans. Measurement of HMGB1 levels within the cerebrospinal fluid (CSF) and serum of neurotrauma patients will be correlated with acute neuronal injury and neurological outcome. Together, the proposed studies will investigate the novel possibility that HMGB1-TLR4 signaling contributes to the development of cerebral edema and increased ICP following TBI. The results of these studies may support the future development of novel therapeutics directed against this pathway to limit neurological injury following head trauma. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a serious medical condition that hospitalizes and disables many Americans, placing a large economic burden on society. Current medical therapies do not effectively control brain swelling, in part, due to a lack of mechanistic understanding regarding the development of cerebral edema following TBI. An improved understanding of these mechanisms at the cellular levels may aid in the discovery of novel therapeutics, which could substantially reduce patient mortality and improve patient outcome. The present application will assess the potential role of neuronal necrosis, secondary to glutamate excitotoxicity, as a causative factor in the development of cellular edema following TBI.

DESCRIPTION (provided by applicant): Intracerebral hemorrhage (ICH), the most common form of hemorrhagic stroke, accounts for up to 15% of all strokes, with 37,000-52,400 Americans suffering an ICH annually. ICH has the highest acute mortality and the worst long-term neurological outcomes of all types of stroke. ICH is caused by a ruptured blood vessel within the brain, leading to the formation of a space occupying hematoma. Hematoma volume is clinically associated with neurological deterioration and higher mortality; however, many ICH patients are poor surgical candidates and/or present with an unfavorable size/location of the lesion, restricting the utility of neurosurgical intervention. Furthermore, efficacious medical treatment options to promote hematoma clearance are lacking, presenting a critical barrier to clinical practice. Our long-term objective is to identify the molecular and cellular pathways which contribute to clot resolution after ICH. This knowledge will provide a framework for pharmaceutical development to improve patient outcomes after ICH. Our pilot data suggest the curry spice, curcumin, promotes hematoma resolution after ICH and may therefore represent a novel and safe treatment option. Specific Aim 1 will test the hypothesis that CD36 mediates curcumin-induced hematoma clearance after ICH. Specific Aim 2 will test the hypothesis that C/EBP-¿ mediates curcumin-induced CD36 expression and hematoma resolution after ICH. Together, the proposed studies will elucidate the molecular and cellular mechanisms which underlie the ability of curcumin to promote hematoma resolution. The results of these studies will provide a framework for pharmaceutical development targeting C/EBP-¿ and/or CD36 to improve clinical outcomes after ICH.

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a leading cause of mortality and long-term disability worldwide. Over 1.7 million Americans suffer a TBI annually and up to 2% of the population currently lives with the long-term neurological consequences of a previous TBI, placing a $76.5 billion annual economic burden on society. Preventative measures reduce injury incidence and/or severity, yet one-third of hospitalized TBI patients die from injuries that are secondary to the initial trauma. Cerebral edema is a life-threatening neurological complication that promotes elevated ICP and leads to clinical deterioration in the hours and days after a TBI. Unfortunately, neurosurgical approaches to control elevated ICP are limited and efficacious medical therapies to control cerebral edema are lacking. A critical barrier to improving patient prognoses remains a lack of clinically effective treatment options after TBI. The objective of this proposal is to implicate NLRP3 as a functional mediator of neurovascular injury after TBI. Specific Aim 1 will test the hypothesis that P2X7 promotes NLRP3 inflammasome activation after TBI. Specific Aim 2 will test the hypothesis that inhibition of the NLRP3 inflammasome attenuates neurological injury after TBI. Expected outcomes of the proposed research include: (1) identification of P2X7 as a key mediator of NLRP3 inflammasome formation following TBI, and (2) demonstration that NLRP3 promotes cerebral edema and worsens neurological outcomes after TBI. These studies may have far-reaching translational implications as the identification of NLRP3 as a key mediator of secondary injury will provide a novel target for therapeutic intervention. These studies also will provide a mechanism of action whereby two-clinically useful therapeutics control post-traumatic edema, providing rationale for rapid clinical translational of these findings after TBI. !

? DESCRIPTION (provided by applicant): Intracerebral hemorrhage (ICH), the most common form of hemorrhagic stroke, accounts for up to 15% of all strokes, with 67,000 Americans suffering an ICH annually. ICH induces the highest acute mortality and the worst long-term neurological outcomes of all types of stroke. ICH is caused by a ruptured blood vessel within the brain, leading to the formation of a space occupying hematoma. Hematoma volume is clinically associated with neurological deterioration and higher mortality, yet a critical barrier to improvin patient outcomes remains a lack of efficacious therapeutic options. Recent work by our laboratory showed remote limb ischemic post- conditioning (RIC) increases cerebral blood flow and improves outcomes after focal cerebral ischemia. Additionally, our pilot data herein showed that RIC reduces neurovascular injury after experimental ICH. Herein, we test the overarching hypothesis that RIC reduces neurological injury after ICH via AMPK-dependent regulation of macrophage polarization. Specific Aim 1 will test the hypothesis that RIC promotes M2 macrophage polarization after ICH via activation of myeloid AMPK. Specific Aim 2 will test the hypothesis that RIC promotes neurological recovery after ICH via activation of myeloid AMPK. Together, these studies will show that RIC provides a non-invasive, clinically feasible, immune mechanism of neurological recovery after ICH. We will also demonstrate that activation of myeloid AMPK reduces long-term injury after ICH.