Coleen M. Atkins - US grants

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a significant health concern, affecting 1.4 million people in the United States each year at a cost of $56 billion. The highest rates of hospitalization and death from TBI occur in the elderly ages 75 or older;and as our population ages, brain trauma in the elderly will become an even more significant health problem. Currently, there are no pharmacological therapies available to elderly people suffering from TBI because of the lack of studies identifying the biochemical changes that are misregulated after TBI. The overall goal of the current application is to elucidate the biochemical signaling pathways that are altered during TBI in the aged animal so that new potential therapeutic targets can be identified to improve functional outcome in aged individuals after brain trauma. Using the parasagittal fluid-percussion head injury (FPI) as a clinically relevant model of TBI, we have found that signaling through the cAMP-protein kinase A (PKA) pathway is impaired after TBI. In both young adult and aged animals, cAMP levels are decreased after TBI. Furthermore, in young adult animals, activation of cAMP-dependent signaling remains chronically impaired for up to 12 weeks after TBI. In Aim 1, we will determine if cAMP and PKA signaling is impaired after TBI in aged animals as compared to young adult animals. In uninjured aged animals, deficits exist already in the ability to increase cAMP levels and activate PKA during learning. Treatment with a phosphodiesterase (PDE) inhibitor, rolipram, to increase cAMP levels improves hippocampal synaptic plasticity and learning in the uninjured aged animal. Our preliminary data indicate that rolipram can rescue the decreases in cAMP levels in the aged animal after TBI. Thus, we hypothesize that treatment with rolipram after TBI will improve signaling through the cAMP-PKA pathway and improve outcome in aged animals. In Aim 2, we will determine if rolipram improves histopathological outcome after TBI in aged animals. A prominent disability after TBI is cognitive dysfunction and in particular, memory formation. The cortex and hippocampus are highly vulnerable during TBI which affects the ability to form and store memories. In Aim 3, we will determine if rolipram improves cAMP- dependent signaling in acute hippocampal slices and ameliorates hippocampal-dependent learning deficits after TBI in aged animals. These proposed studies will identify the biochemical mechanisms misregulated by trauma in the aged brain and expand the potential therapeutic interventions available to elderly patients suffering from brain trauma to improve cognition and facilitate recovery. PUBLIC HEALTH RELEVANCE: More than 1.4 million individuals per year are afflicted with a traumatic brain injury (TBI) and the ability to withstand brain injury diminishes with age. The research proposed in this grant application is to develop a therapy that reduces pathology in the brain after TBI and improves behavioral recovery in the aged population.

DESCRIPTION (provided by applicant): More than 3.17 million Americans are coping with long-term disabilities due to traumatic brain injury (TBI). Since most TBI research focuses on developing acute treatments to prevent or minimize long-term disabilities, chronic TBI survivors represent a large, underserved population. Chronic TBI survivors could significantly benefit from therapies that promote endogenous synaptic plasticity mechanisms. In both experimental models of TBI and in human TBI, previous studies have found that the hippocampus is highly vulnerable to brain injury. Although often not directly mechanically injured by the head injury, in the weeks to months following TBI, the hippocampus undergoes atrophy and exhibits deficits in long-term potentiation (LTP), a persistent increase in synaptic strength that is considered to underlie learning and memory. The overall objective of this grant proposal is to understand the molecular mechanisms that contribute to hippocampal-dependent LTP deficits and learning impairments in the weeks to months after TBI. Given the critical role of the hippocampus in forming declarative memories, we propose that identifying the molecular mechanisms that underlie the deficits in hippocampal LTP after TBI could provide therapeutic targets to improve hippocampal-dependent learning after TBI. To this end, our laboratory has found that activation of extracellular signal-regulated kinase (ERK) and one of its downstream effectors, the transcription factor cAMP-response element binding protein (CREB), is significantly impaired in the hippocampus from 2 weeks to 3 months after TBI. ERK and CREB are required for long-lasting forms of LTP as well as hippocampal-dependent memory formation. Thus, we hypothesize that a pharmacological treatment which stimulates ERK activation in the hippocampus will improve hippocampal- dependent learning deficits at chronic time points after TBI. Indeed, our preliminary data demonstrate that there are deficits in the activation of ERK in TBI animals after a hippocampal learning task and that this can be rescued with a phosphodiesterase inhibitor. Furthermore, when animals at 3 months after TBI receive a phosphodiesterase inhibitor prior to training, hippocampal-dependent learning deficits are ameliorated when assessed using the Morris water maze task and contextual fear conditioning. In Aim 1, we will identify the underlying molecular mechanisms that contribute to the deficits in ERK and CREB activation in the hippocampal after TBI. In Aim 2, we will test the hypothesis that increasing ERK and CREB activation will rescue hippocampal LTP after TBI. In Aim 3, we will determine if increasing ERK and CREB activation improves hippocampal-dependent learning deficits after TBI. This project is highly supported by an established group of investigators who provide expertise in the molecular mechanisms of hippocampal-dependent LTP, learning and memory, and TBI. The proposed studies will provide new insights into the molecular mechanisms of hippocampal-dependent learning impairments after TBI, and develop therapeutic strategies to improve hippocampal-dependent learning for chronic TBI survivors. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a major cause of disability in the United States. There are currently no treatments to improve learning and memory functioning in chronically disabled TBI survivors. This grant will identify the biochemical mechanisms that underlie learning and memory disabilities after TBI and investigate whether an FDA-approved drug can restore learning and memory functioning in the weeks to months after TBI.

DESCRIPTION (provided by applicant): Previous studies have emphasized that after brain and spinal cord injury there are dramatic reductions in levels of the second messenger cyclic adenosine monophosphate (cAMP), a critical intracellular signaling molecule in neurons and inflammatory cells. Over the last funding period, our laboratory has found that after traumatic brain injury (TBI) cAMP reductions participate in the vulnerability of the posttraumatic brain to secondary injuries such as hemodynamic alterations, inflammation, and long-term synaptic dysfunction. Phosphodiesterase 4 (PDE4) is the major enzyme responsible for cAMP hydrolysis in the brain and currently is an important molecular target for the treatment of various human neurological diseases including neurotrauma. Studies we have completed during the previous funding period have emphasized the complexity of the response to trauma of different PDE4 isoforms in terms of their various time-dependent cellular responses. The characterization of these cellular and biochemical changes are critical for the development and testing of new inhibitors against specific PDE4 isoforms. In the current proposal, we will address several knowledge gaps that hamper clinical development of PDE4 inhibitors for the treatment of TBI, including the identification of PDE4 isoforms in specific inflammatory cell populations as well as assessing the effects on isoform-selective PDE4 inhibitors on posttraumatic inflammation. Another exciting recent discovery that will be investigated is the ability of PDE4B isoform-specific inhibitors to significantly reduce chronic cognitive deficits, thereby providing a novel therapeutic strategy for people living with TBI. Based on our previous and new preliminary data, we therefore propose the following four aims: 1) To investigate the contribution of PDE4B to acute inflammation after TBI, 2) To determine if inhibition of PDE4B acutely after TBI improves pathology and behavioral outcome, 3) To test whether a PDE4B isoform-selective inhibitor improves chronic cognitive deficits, and finally, 4) To directly determine if loss of PDE4B improves outcome and loss of PDE4D worsens outcome after TBI. These studies will determine which specific PDE4 isoforms need to be selectively inhibited at different therapeutic time windows after TBI to reduce inflammation and pathology, and promote recovery in three therapeutic time windows, acute, subacute and chronic. Together, these studies will provide critical information regarding the precise cellular events by which isoform-selective PDE4 inhibitors produce their benefits, and provide evidence-based mechanistic data to support the use of PDE4 inhibitors in acute, subacute, and chronic therapeutic time windows after TBI. This proposal is supported by a multidisciplinary, multi-institutional research team with experience in experimental TBI models, PDE4B and PDE4D knockout mice, and a pharmacological partner with an established record in CNS drug discovery. These studies will provide the necessary preclinical data for the clinical translation of these novel agents for the treatment of TBI.

Previous studies have emphasized that after brain and spinal cord injury there are dramatic reductions in levels of the second messenger cyclic adenosine monophosphate (cAMP), a critical intracellular signaling molecule in neurons and inflammatory cells. Over the last funding period, our laboratory has found that after traumatic brain injury (TBI) reductions in cAMP participate in the vulnerability of the posttraumatic brain to secondary injuries such as hemodynamic alterations, inflammation and long-term synaptic dysfunction. Phosphodiesterase 4 (PDE4) is the major enzyme responsible for cAMP hydrolysis in the brain and currently is an important molecular target for the treatment of various human neurological diseases including neurotrauma and Alzheimer's disease. PDE4 inhibitors improve chronic learning and memory deficits after TBI and reverse learning deficits in an APP/PS1 transgenic mouse model of Alzheimer's disease. In the current proposal, we will address several knowledge gaps that hamper clinical development of PDE4 inhibitors for the treatment of TBI and Alzheimer's disease, including the involvement of specific PDE4 isoforms in cognitive dysfunction. The overall hypothesis of this proposal is that a PDE4 isoform-selective inhibitor will improve chronic cognitive deficits after TBI in wild type mice and in a mouse model of Alzheimer's disease. To test this hypothesis, we propose to utilize APP/PS1 mice which recapitulate several features of Alzheimer's disease. Furthermore, these mice have exacerbated pathology and inflammation after TBI. These studies will determine which specific PDE4 isoforms need to be selectively inhibited during in the evolution of Alzheimer's disease after TBI to promote cognitive recovery, prevent inflammation and reduce axonal damage. This proposal is supported by a multidisciplinary, multi- institutional research team with experience in experimental TBI models, Alzheimer's disease mouse models and a pharmacological partner with an established record in CNS drug discovery. These studies will provide the necessary preclinical data for the clinical translation of these novel agents for the treatment of TBI and Alzheimer's disease.