2009 — 2012 |
Badaut, Jerome |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Aqp4 and Jnk Inhibition Together Reduce Edema and Excitotoxic Injury in Jtbi
DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is common in adolescents and young adults and is frequently associated with a high risk for long-term disability and mortality. Unique to pediatric TBI is the increased danger of developing cerebral edema, a phenomenon thought to be related to higher brain water content in the young and to developmental differences of the brain's response to injury. Likewise, the developing brain is more susceptible to excitotoxic, apoptotic and inflammatory injury at a time when plasticity is critical in promoting endogenous recovery as well as in response to exogenous pharmaceutical treatment. Recent studies have demonstrated that two novel proteins/pathways (aquaporins, AQPs;c-Jun N terminal kinase, c-JNK) play critical roles at different overlapping points in the cascade of events after ischemic and traumatic brain injury. AQPs are a unique class of water channels and AQP4, the most abundant brain AQP, plays a critical role in edema formation and constitutes an excellent molecular candidate for the development of novel agents to reduce post-TBI edema. AQPs also recently have been shown to participate in other pathways that contribute to brain injury and repair. JNK pathways, mediated by glutamate-calcium activation, trigger mitochondrial cascades of programmed cell death, accelerate MAP kinase neuronal death and participate in production of proinflammatory mediators from glial cells. Of great clinical interest is that in the last two years novel agents have been developed to inhibit these two pathways: (i) small interference RNA (siRNA) against AQP4, siAQP4;and (ii) D-JNKI1, a protease-resistant JNK-inhibiting peptide. This proposal will test the hypothesis that these novel agents can inhibit these two proteins/pathways and that when combined they will have a synergistic effect in reducing magnetic resonance imaging, histological and behavioral outcomes in a juvenile TBI model. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is common in children and adolescents and is frequently associated with a high risk of long-term disability and mortality. Unique to pediatric TBI is the greater danger of developing cerebral edema, as well as the greater susceptibility to excitotoxic, apoptotic and inflammatory injury. Recent studies have demonstrated that two novel proteins/pathways (aquaporins, AQPS;c-Jun N terminal kinase, c-JNK) play critical roles in the cascade of events after ischemia and TBI. Novel agents have been developed to inhibit these two pathways: (i) small interference RNA (siRNA) against AQP4, siAQP4;and (ii) D-JNKI1, a protease-resistant JNK-inhibiting peptide. This proposal will test the hypothesis that these novel agents will inhibit these two proteins/pathways and this will have a synergistic effect in reducing magnetic resonance imaging, histological and behavioral outcomes in a juvenile controlled cortical impact model of TBI.
|
1 |
2014 — 2018 |
Badaut, Jerome |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Caveolin 1 Role in Hemorrhagic Injuries
Traumatic brain injury (TBI) is common and frequently associated with potential long-term disability and mortality. TBI is primarily a consequence of a direct or indirect biomechanical force on brain tissues and followed by secondary injury cascade, ranging from changes in cerebral blood flow, increased intracranial pressure. Blood-brain barrier (BBB) dysfunction, edema formation, inflammation, excitotoxicity and cell death. To date, treatment strategies targeting neuronal rescue after TBI have not been clinically successful; therefore, treatments targeting the expanded vascular neural network (VNN) need to be developed not only for TBI patients but also for those with subarachnoid (SAH) and intracerebral hemorrhage (ICH). Recent studies have demonstrated that Caveolins (Cav) play a central role in several vascular diseases or injuries, with a potential protective role by inhibition of endothelial nitric oxide synthase (eNOS) and activation of c-Jun N terminal kinase (c-JNK). Both of these pathways play a detrimental role after injury in the VNN. A synthetic peptide, Cav-AP, reproduces the endogenous Cav functions by binding and inhibiting eNOS and JNK, and is now in development for cancer treatment. The role of Cav-1 will be investigated in a TBI rat model, by: i) decreasing Cav-1 with siRNA; and ii) mimicking Cav-1 functions by injection of Cav- AP after injury. We will also investigate the molecular mechanisms by testing: i) the level of activation of eNOS and JNK after TBI and Cav-AP treatment within the VNN, ii) with injection of an eNOS inhibitor (LNIO) and iii) treatment by a peptide D-JNKI inhibitor of the JNK pathway. Finally, Cav-AP will be tested as a potential treatment in SAH and ICH. Understanding the roles of Cav-1, eNOS and the JNK pathway in brain vascular system will provide avenues for development of therapeutic targets towards the VNN in hemorrhagic diseases.
|
1 |
2019 |
Badaut, Jerome Bix, Gregory Jaye [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Perlecan Therapy For White Matter and Cognitive Impairment in Closed Head Injury With Long-Term Dysfunction (Child)
PROJECT SUMMARY / ABSTRACT Juvenile traumatic brain injury, even when in the most commonly occurring mild form (juvenile mild TBI, jmTBI), is a major public health issue that is associated with significant long-term morbidity and is a risk factor for cognitive decline. To date, very little is known about the pathological processes during the first week after jmTBI as well as their long-term potential as vascular contributions to cognitive impairment and dementia (VCID). It is critical to have a better understanding of the long-term changes in order to accurately develop new treatments to minimize or prevent VCID. We previously demonstrated long-term grey matter changes in the neurovascular unit (NVU), blood-brain barrier (BBB) and brain extracellular matrix proteins in experimental moderate/severe juvenile-TBI. However, as long-term white matter (WM) changes also occur and have been implicated in accelerated cognitive decline in clinical and pre-clinical studies, we hypothesize that early post- jmTBI vascular dysfunction with degradation of extracellular matrix (ECM) proteins significantly contributes to long-term WM injury and VCID. Intriguingly, in various models of WM injury and VCID, a significant acute increase in WM expression of the vascular ECM heparan sulfate proteoglycan, perlecan, as well as its neuroprotective and angiogenic C-terminal protein fragment domain V (DV), is observed. We hypothesize that in the context of vascular dysfunction and ECM degradation, DV is acutely generated in WM after jmTBI and plays a significant, potentially beneficial role to WM's response to- and long-term cognitive consequences of jmTBI that could be therapeutically exploited. To investigate this hypothesis, we have developed a novel mouse jmTBI model of Closed Head Injury with Long- term Dysfunctions (named CHILD) to investigate early WM vascular changes as a model of VCID. Specifically, we propose to determine the role of the extracellular matrix protein perlecan DV in WM neurovascular unit changes and long-term cognitive decline after jmTBI as a model of VCID, and to determine the therapeutic potential and endothelial cell mechanism of action of recombinant domain V in jmTBI as a model of VCID.
|
0.957 |
2021 |
Badaut, Jerome Obenaus, Andre [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Caveolin-1 Contributes to the Long-Term Function and Structure of the Neurovascular Unit After Juvenile Concussion @ University of California-Irvine
Summary Project The majority of traumatic brain injury (TBI) is mild in nature but is known to elicit long-term consequences, including emergence of dementia and accelerated age-related declines. The highest-at-risk group are children whose brains are still undergoing development. This proposal will investigate the short- and long-term, cellular and molecular changes in the brain following juvenile mTBI (jmTBI) with the goal to intelligently develop new therapeutic options. Caveolin-1 (Cav-1) is an abundant structural protein involved in caveolae formation and cell signaling which is expressed in cerebral endothelial cells and in astrocytes, key components of the neurovascular unit (NVU). Recent development of a compound to target the Caveolin Scaffolding Domain (CSD), a complex that compartmentalizes structural proteins (e.g. claudin-5) and signaling molecules (e.g. eNOS), has provided tools to explore the role of Cav-1 in acquired neurological disease. After stroke, we found increased Cav-1 expression and Cav-AP treatment was beneficial for post-injury recovery. However, consensus is lacking whether Cav-1 exhibits beneficial or deleterious actions in other acquired brain disorders, such as jmTBI. Our model of jmTBI exhibits accelerated loss of cognition associated with decreased vascular function over their lifespan. We therefore will test the hypothesis that dysfunction in neurovascular coupling after jmTBI can be prevented by modulation of Cav-1 signaling, blunting accelerated hippocampal and cortical aging. Aim 1 will demonstrate that Cav-1 is critical for maintaining NVU functionality. We examine the role of vascular Cav-1 in male & female jmTBI mice in normal (WT), vascular Cav-1 deficient mice (Cav-1-/-) and in Cav-AP treated mice. We believe that jmTBI mice treated with Cav-AP will exhibit vascular recovery, whereas the loss of Cav-1 will worsen NVU outcomes. In Aim 2 we will examine how Cav- 1 in reactive astrocyte processes influences progression of jmTBI. We will modulate Cav-1 expression directly in astrocytes by injecting AAV-GFAP-Cav-1-shRNA and AAV-GFAP-synCav-1 in control and injured mice and quantify vascular recovery and behavioral outcomes. Increased astrocytic Cav-1 will be associated with improved NVU properties and cognitive outcomes. In Aim 3 we will examine male & female mice over their lifespan and examining if increased Cav-1 blunts accelerated brain aging that we have observed after jmTBI. We will assess behavioral, neuroimaging and histological outcomes. jmTBI mice treated with Cav-AP will exhibit improved outcomes related to enhanced NVU function and integrity. In sum, the proposed research is a critical first step in examining the role of Cav-1 in jmTBI and if therapeutic intervention can lead to enhanced NVU stability and function and thereby moderate accelerated aging.
|
0.948 |