Below is the final program schedule for the 2011 meeting including abstracts.
Wednesday, March 16
5:30pm-8:30pm: Opening Reception
• 5:30pm-6:30 pm: Appetizers and Complimentary Margaritas, Beer, Wine
• 6:30pm-7:30pm: "A Tribute to Chuck Ribak"
Lee A. Shapiro, Steven Danzer, Dan McCloskey
• 7:30pm-8:30pm: "Activity-induced dendritic processing: structural and functional consequences."
David Wells, PhD;
Participants:
Christine Gall, PhD "BDNF, integrins, and cytoskeletal remodeling."
Mark Yeckel, PhD "Rogue waves? What are intraneuronal Ca2+ waves and what are they good for?"
In this session we will present data showing several ways in which processing may occur in neuronal dendrites. Activity-induced changes in dendrites include mGluR-mediated, IP3 -dependent intracellular calcium waves, alterations to the cytoskeleton, and stimulation of new protein synthesis. Although these events must take place in the same temporal and spatial window, they are often discussed as singular events. Our goal is to bring these areas of research together to show how the relationships between these events may result in structural changes at the synapse and discuss how their interplay may have functional consequences on synaptic signaling.
Thursday, March 17
6:30am-7:00am: BREAKFAST
7:00am-8:30am: "Pathophysiology of Migraine Headache"
Frank Porreca, Ph.D., Chair
Colin Willis, Ph.D., University of New England
Ian Meng, Ph.D., University of New England
Todd Vanderah, Ph.D., University of Arizona
Migraine headache was once thought to be predominately of vascular origin but it is now increasingly appreciated that its genesis and progression also involves maladaptive changes in the nervous system. Migraine represents the most common neurological disorder affecting up to 33% of women and 13% of men at some point in their lives. Despite its widespread prevalence, the pathophysiology that leads to migraine headache is still poorly understood and pharmacological treatment is only effective in about 50%, or less, of migraine sufferers. Developing new treatments with greater efficacy than those currently available is limited, in part, by a lack of new therapeutic targets.
Dr. Willis will address the role of the neurovascular unit in initiation of headache pain and in relation to the relief of headache pain by anti-migraine medications such as the triptan drugs. Dr. Meng will focus on the adaptive changes that result from overuse of medications that are used to treat migraine including opiates. These medications can result in a loss of diffuse noxious inhibitory controls (DNIC) or (i.e., conditioned pain modulation). This mechanism has been prominently observed as a part of multiple states of dysfunctional pain (e.g., fibromyalgia). Dr. Vanderah will speak about the role of cortical hyperexcitability in activation of trigeminal afferent fibers innervating the dura. His studies will explore the contribution of cortical spreading depression mechanisms in generation and maintenance of migraine pain.
8:30am -9:30am: "Biomarkers in CNS Injury"
Ron Hayes "Use of Biomarkers in Diagnostics"
There is growing awareness of the inadequacies of the current diagnostic categories for traumatic brain injury (TBI), which are largely descriptive. Clinical investigators have recognized that serum biomarkers of TBI could significantly facilitate development of diagnosis acute CNS injuries based on objective neurochemical measurements. This presentation reviews approaches to discovery and clinical validation of novel biomarkers of mild, moderate and severe TBI. In addition, clinical applications of the biomarkers will also be presented.
Ross Bullock "Clinical Use of Biomarkers"
Many categories of "biomarkers" have been proposed to allow better diagnosis and tracking of the status of the brain after TBI. These include blood Analytes, brain ECF analytes MRI spectrA and derived hemodynamic spectra to name a few. None have so far proved ideal for clinical use. We will review the clinical requirements for biomarkers and the data to support candidate analytes and compare progress to other clinical situations such as HIV/AIDS. We will also discuss validation approaches for new biomarker candidates.
9:30am-11:00am: "STROKE: From Restoration to Rehabilitation"
Michael Chopp
Steven C. Cramer, MD
Stroke remains a leading cause of human disability. Currently, acute stroke therapies reach a minority of patients, and many so treated nonetheless have significant long-term deficits. Therapies targeting brain repair have the potential to help a large fraction of patients with stroke. A number of such therapies are under study in preclinical and human clinical trials. Treatment approaches include small molecules, large molecules such as antibodies and growth factors, brain stimulation, robotic devices, cell therapies, and more. Treating the brain in this context introduces complexities; brain repair is optimized when administered according to certain principles. Examples including treating with respect to the time sensitivity of repair targets, and the experience-dependent nature of plasticity and repair. A key principle in this context is the need to select patients whose biological state corresponds to the needs of the therapy. A number of approaches are under consideration in this regard, including measurement of key white matter tracts to best stratify patients. Brain repair is an emerging approach to post-stroke therapy that might one day help reduce disability among a large fraction of patients suffering from stroke.
Steve Cramer will discuss how these therapies will be individualized to patient's needs, and prescribed to maximum effect. Michael Chopp will talk about molecular and cellular mechanisms that contribute to brain plasticity and promote functional recovery after cell-based and pharmacological restorative treatments for stroke and neural injury.
11:00am-12:00pm: "Intracerebral Hemorrhage: The Problematic Role of Cerebral Edema"
Guohua Xi, M.D. "Brain Edema following Experimental ICH"
William Powers "Clinical Evidence of Edema in ICH"
Intracerebral hemorrhage (ICH) is a common and often fatal subtype of stroke that produces severe neurologic deficits in survivors with 30-day mortality rates of 35-52%. The past decade has resulted in a rapid increase in our knowledge of the brain edema mechanisms following experimental ICH. Animal studies have indicated a role for clot-derived factors as well as the initial physical trauma/mass effect due to the hemorrhage. The coagulation cascade, complement activation, hemoglobin breakdown products (particularly iron) and inflammation all play a role in ICH-induced brain edema and may provide new therapeutic targets. The mechanisms underlying and the clinical importance of cerebral edema following ICH in humans are much less clear. Neuroimaging studies do not support peri-hematomal ischemia as a cause of edema. Recently, barotrauma from pressure waves that propagate through the intracranial contents has been suggested as a common mechanism of brain injury in both ICH and traumatic brain based on similar abnormalities of cerebral blood flow and metabolism in the two conditions. Recent data demonstrating contralateral hemispheric damage in patients with acute ICH provides further support for this theory. The clinical importance of edema has been more difficult to demonstrate. Although the area of peri-hematomal edema on CT or MRI increases in the several weeks following ICH, this growth is not associated with early clinical deterioration or worse eventual outcome. Hopefully, the next decade will bring further knowledge about the underlying mechanisms of ICH-induced brain damage as well as new therapeutic interventions for this devastating form of stroke.
12:00pm-12:30pm: "Clinical Pathophysiology of Migraine"
David Dodick
12:30pm: LUNCH and Afternoon free
5:00pm-6:30 pm: "A Cross-Species Consensus on the Neurobiology of Normal Aging: From Single Unit Activity to Behavioral Output"
Chair: Carol A. Barnes
Speakers:
Lesley Schimanski , "Do old rats learn new places? Reduced activity of aged hippocampal place cells during spatial encoding."
Sara Burke, "Rat and monkeys show age-associated deficits in perirhinal cortical-dependent pattern separation."
Nathan Insel, "Age-related changes in neural oscillations in rat frontal cortex."
Doug Rosene, "White matter changes as a common denominator for neuronal dysfunction and cognitive aging in the Rhesus monkey."
6:30 pm-7:00pm: "Discoveries and Clinical Applications Emerging From New Approaches to Measure the Functional Architecture of the Human Brain"
Randy L. Buckner, Ph.D.
Study of amyloid deposition in Alzheimer's disease (AD) reveals a stereotypic pattern of vulnerability that targets cortical regions linked to a specific brain network known as the 'default network.' In this talk, recent observations will be reviewed the suggest properties of activity- and metabolism within the default network set the context for the pathological cascade of AD. At the earliest stages of the disease, atrophy, metabolism disruption, and functional disturbances can be observed in the default network, including in clinically normal individuals individuals who show amyloid deposition. I will conclude by speculating why regions within the default network might be particularly vulnerable to AD pathology and the implications for study of disease risk and intervention.
DINNER: Cash Bar
7:30pm-8:00pm : Keynote Speaker
Lynn Nadel, "Deciphering the Hippocampus: A Personal Perspective"
Friday, March 18
6:30am-7:00am BREAKFAST
7:00am-8:30am: "Visualization of inflammation within the central nervous system"
Organizer:
Gregory Wu, MD, PhD
Emma Wilson, PhD
Aaron Johnson, PhD
As an immune-specialized organ, the central nervous system (CNS) employs unique regulatory mechanisms during immunity. These critical cellular and molecular features come into play during infection and auto-immunity of the CNS, which are relevant to human diseases such as encephalitis and multiple sclerosis (MS). Recent advances in imaging have afforded the opportunity to visualize immune cell interactions with glia and neurons within the CNS. The goal of this session is to identify and characterize neural-immune interactions in animal models of human CNS disease. Dr. Wilson will address this goal by discussing a model of parasitic infection of the brain. The Wilson lab investigates mechanisms of immune control in the brain during Toxoplasma infection. This is an extremely common parasite that requires a continuous T cell response within the CNS to maintain latency, yet there are no apparent pathological consequences to such CNS infiltration. Mechanisms of cell migration including generation of matrix scaffolds, chemokine guidance and the role of proteases will be discussed. Dr. Johnson will address the goal of this session by presenting work on a viral-based mouse model of MS. Specifically, he will discuss imaging results on the extent to which CD8 T cells actively engage virus infected neurons in mice infected with Theiler's murine encephalomyelitis virus. Using intravital 2-photon microscopy, Dr. Wu will present data on the interactions between innate immune cells and axons in an animal model for MS. Specifically, the cause and effect relationship between both microglia and infiltrating dendritic cells with injured spinal cord axons will be characterized. These imaging studies offer complimentary views on how immune and CNS cells interact to promote effective immunity as well as pathologic conditions.
8:30am-10:00am: "Are anesthetics neuroprotective or neurotoxic?"
Huafeng Wei, MD, PhD "Neuroprotection and neurotoxicity of anesthetics: a double edge sword"
Short exposure of anesthetics at low concentrations provide neuroprotection by causing a moderate increase in cytosolic calcium concentration through calcium release from the intracellular calcium stores via activation of InsP3 receptors (InsP3R) or ryanodine receptors. However, prolonged exposure of anesthetics at high concentrations causes cell apoptosis by causing abnormal and excessive calcium release from intracellular stores. Our studies have suggested that abnormal calcium release from endoplasmic reticulum via over activation of InsP3R or ryanodine receptors cause cell apoptosis and neurodegeneration in both tissue cultures and animal models. Isoflurane modulates InsP3R calcium channel opening in the presence or absence of its endogenous agonist InsP3. Alzheimer's presenillin-1 or Huntington's Huntingtin protein mutation may sensitize InsP3R activation by anesthetics and worsen anesthetics mediated pathological protein aggregation and cell death. In addition, postnatal rats born from mothers exposed to isoflurane at low concentration (1.2%) for 6 hr demonstrated decreased spontaneous apoptosis in their brains and transiently improved memory, while exposure of high concentration of isoflurane (3%) for 6 hr to pregnant rats induced significant neuroapoptosis in developing fetal brains. Preconditioning with short exposure of isoflurane inhibit cell damage induced by prolonged exposure of isoflurane in different types of neuronal tissue cultures. Our recent study also suggested that preconditioning with short exposure of 1.5% isoflurane (30 min) itself did not cause obvious neuronal apoptosis, but significantly inhibited neuronal apoptosis induced by prolonged exposure of 1.5% isoflurane (6hr) in developing rat brains of 7 day old rats. There was no significant changes of LC3 II and Beclin-1 levels (biomarkers of autophagy activity) with either isoflurane mediated preconditioning or neurotoxicity. Overall, our studies suggest that isoflurane may be both neuroprotective and neurotoxic, depending on the concentrations and exposure duration.
Zhiyi Zuo, MD, PhD, "Anesthetic preconditioning- and postconditioning-induced neuroprotection"
Ischemic brain injury is implicated in the pathophysiology of stroke and brain trauma, which are among the top 10 killers in the USA. Up till now, clinically practical methods to reduce ischemic brain injury have not been well established yet.
Two promising approaches, preconditioning and postconditioning, for limiting ischemic injury have been focuses of research in recent years. Ischemic preconditioning is a phenomenon in which brief episodes of sub-lethal ischemia induce a robust protection against the deleterious effects of subsequent prolonged ischemia in many organs, including brain and heart. There are two temporal phases: acute and delayed. The acute phase is considered to be mediated by functional changes of existing proteins, is present within minutes, and disappears 2-3 hours later. The delayed phase develops hours after the preconditioning event, often requires new protein synthesis, and is sustained for several days.
We and other people have shown that volatile anesthetics, commonly used general anesthetics in clinical practice, can induce a preconditioning effect in the brain. This effect is concentration- and time-dependent. The delayed phase of volatile anesthetic preconditioning-induced neuroprotection may be agent-specific. The anesthetic preconditioning-induced neuroprotection is long-lasting. Multiple intracellular signaling molecules including mitogen-activated protein kinase, inducible nitric oxide synthase and ATP-activated potassium channels have been implicated in the anesthetic preconditioning-induced neuroprotection. B-cell lymphoma-2 may be an effector for this protection.
Modification of reperfusion process can reduce reperfusion-induced injury. This phenomenon is called ischemic postconditioning. Application of anesthetics after brain ischemia also can provide neuroprotection and is named anesthetic postconditioning-induced neuroprotection. This protection is also time- and concentration-dependent. ATP-activated potassium channels and calcium/calmodulin-dependent protein kinase II may be involved in the anesthetic postconditioning in the brain.
Interestingly, the volatile anesthetic preconditioning- and postconditioning-induced neuroprotection can be additive.
Stephanie J. Murphy, VMD, PhD, "Sex and age may alter anesthetic preconditioning neuroprotection"
Brain preconditioning relies on the fact that prior exposure to relatively minor insults, chemicals, or pharmacological agents can increase the brain's tolerance to future, more injurious events. Clinically, there is much interest in determining the feasibility of pharmacologically preconditioning the human brain with anesthetics in the perioperative arena and the impact of such preconditioning on perioperative stroke. Such anesthetic preconditioning of the brain during neurosurgical, vascular or cardiovascular vascular procedures may therefore decrease or even delay injury from perioperative stroke as well as expand the therapeutic window for other prospective neuroprotectants. Women, however, may have a greater perioperative stroke risk than men for these procedures. Because experimental studies examining anesthetic preconditioning and its neuroprotective mechanisms in ischemic brain have predominantly used young adult male animals, it is unclear how sex and age may modify the brain's response to inhalational anesthetic preconditioning and subsequent injury. Furthermore, the underlying mechanisms for sex and age differences in volatile anesthetic effects on perioperative stroke outcomes are not well characterized and offer potential factors for optimizing anesthetic management of patients undergoing procedures at risk for perioperative stroke. This plenary presentation will review what work has been done evaluating the effects of sex and age on the brain's response to anesthetic preconditioning relative to ischemic and other types of injury and will discuss the possible mechanisms that are currently under investigation.
10:00am-11:30am: "Epidemiology of Stroke and Vascular Disease"
George Howard "The Mystery of Geographical Variation"
Clinton Wright "Cognitive Function after Stroke"
Cerebral small vessel damage is increasingly recognized as a risk factor for clinical stroke, disability, gait problems, and cognitive decline. However, the relative importance of specific vascular risk factors such as high blood pressure, insulin resistance, and dyslipidemia need to be clarified, as do the mechanisms through which these factors impact brain function by causing brain atrophy, white matter damage, frank infarctions and hemorrhages. Large population-based studies have begun to tease apart some of these processes, but much work needs to be done and unanswered questions remain regarding the importance of genetic influences and cognitive reserve
11:30am-12:30pm: "Epilepsy: Basic to Clinical"
Organizer: David Labiner
Hemant S Kudrimoti
Robert S Sloviter
12:30pm: LUNCH and Afternoon free
5:00pm-6:30pm : "Parkinsons Disease"
Michael G. Kaplitt, MD, PhD, "Advances in Clinical Gene Therapy for Parkinson's Disease"
Gene therapy for neurological disorders has evolved in recent years from a purely basic science tool to an experimental clinical therapeutic with realistic possibilities for future widespread application. The first human clinical of in vivo gene therapy transferred the gene for glutamic acid decarboxylase (GAD) into the human subthalamic nucleus (STN) using an adeno-associated virus (AAV) vector. Clinical improvements and a strong safety profile in an open-label phase I led to a randomized, double-blind, sham-surgery controlled phase 2 trial which has now demonstrated significant improvements in the AAV-GAD group compared to shams, with no therapy-related adverse events. Alternative approaches utilize the gene for Neurturin, which activates neurotrophin receptors as well as two strategies to improving local striatal dopamine production, all of which are currently in human clinical trials. If the current evidence of efficacy and outstanding safety profile of some of these strategies sustain in later studies, this could herald the widespread application of gene-based therapies for Parkinson's disease and facilitate applications for other neurological and psychiatric diseases.
Raj Ratan, MD, PhD,"Novel, iron dependent molecular targets of neuroprotection in Parkinson's disease"
Organic small molecule iron chelators have been shown to protect against cell death in vitro and in disease models of Parkinson's disease, stroke, Alzheimer's disease, and multiple sclerosis. The traditional view is that the pluripotency of these clinically approved agents (e.g. desferoxamine) derives from their ability to inderdict the generation of toxic free radicals by preventing iron-catalyzed oxidation. Here, we present data that suggests that iron, 2-oxoglutarate, and oxygen dependent dioxgyenases which also function as cellular oxygen sensors are a target for iron chelator mediated neuroprotection. Transcriptional and non-transcriptional targets for these interesting class of enzymes will be discussed along with the implication for disease therapeutics.
David Eidelberg, MD,"Metabolic Brain Networks in Parkinson's Disease"
Network analysis of functional brain imaging data is an innovative approach to the study of circuit abnormalities in neurodegenerative diseases. In Parkinson's disease, spatial covariance analysis of resting state metabolic images has been used to identify specific regional patterns associated with motor and cognitive symptoms. With functional imaging, these metabolic networks have recently been used to measure system-related progression and to evaluate the effects of novel treatment strategies. Ongoing developments in network applications are likely to enhance the role of functional imaging in the investigation of neurodegenerative disorders.
6:30pm-7:00 pm: "The History of Electrophysiology: Standing on the Shoulders of Giants"
Douglas Stuart, PhD
Intracellular (IC) recording of action potentials in neurons of the vertebrate central nervous system (CNS) was first reported by John Eccles and two colleagues, Walter Brock and John Coombs, in Dunedin, NZL in 1951/1952 and by Walter Woodbury and Harry Patton in Seattle, WA, USA in 1952. Both groups studied spinal cord (SC) motoneurons (MNs) of the adult cat and the USA team also recorded from interneurons (INs). In this review, I will first discuss the precedents to their notable achievement, beginning briefly with 19th and early 20th C work, but focusing on the immediate post WWII groundwork. After summarizing the 1951/1952 achievements of the above NZL and USA groups, I will discuss the first IC-recording in non-mammalian and invertebrate MNs and INs and some of the technical advances that then occurred. My review will conclude with discussion of the challenge of integrating new findings using molecular genetics with cellular and systems approaches. Present-day neuroscientists using patch-clamp recording, cell staining techniques, unanaesthetized in vivo preparations, and in vitro slices and blocks of CNS tissue owe much to the IC-recording pioneers.
DINNER: Cash Bar
7:30pm-8:30pm: Evening Keynote speaker "Addressing the key CNS drug discovery and development challenges: a great opportunity for Academia and Pharma to work together"
Philippe Walker
Vice-President, iMED Science Unit
CNSP Montréal
The world is facing an emerging medical and social crisis due to the increased burden of CNS diseases. Both Pharma and Academia have a critical role to play in addressing this problem. CNS illnesses and Pain can be debilitating and we are not finding new effective therapeutic solutions fast enough. We have to find new more strategic ways to bring our resources and brain power together to address this growing need. In this presentation I discuss, from a drug-hunter perspective, the main areas where Academia and Pharma could collaborate more closely and strategically to advance our understanding of these diseases and facilitate the discovery of novel therapeutic solutions. I will outline the key scientific challenges for psychiatry, neurology and analgesia drug discovery.
In psychiatry, discovering new drugs is challenging because we understand pathophysiology poorly, because psychiatric illnesses are very heterogeneous and because we lack objective measures of illness. Current Alzheimer symptomatic treatments are not effective; discovering disease-modifying drugs is challenging because Alzheimer's disease starts many years before symptoms are apparent, and we currently do not have accurate early diagnostic tools. Discovering drugs to treat pathological pain is slow and difficult because animal models do not accurately predict clinical outcomes. Pain is another heterogeneous disease and we need better patient segmentation approaches.
Academia has the strengths and expertise to provide solutions to the central obstacles hampering CNS and Pain drug development, and working together with Pharma, we stand a much better chance of achieving breakthroughs in understanding and treating these diseases. We need new more strategic approaches to partnering. Consortia and other innovative "pre-competitive" collaborations serve as promising models to share risk and rewards in the discovery and development of new therapies. Together, through innovative partnering, we can make a difference in these dreaded diseases.
Saturday, March 19
7:00am-8:00am: BREAKFAST
8:00am-9:00am: "Zipping to pain relief: The role of PKMz in pain chronification"
The mechanisms underlying the chronification of pain are poorly understood; however, gaining further insight into this process may lead to therapeutic opportunities with the potential to better treat or even reverse chronic pain. Long-term potentiation (LTP) of synaptic transmission is an important feature of learning and memory and of pain amplification. Evidence from the learning and memory area indicates that an atypical PKC called PKMz is required to maintain LTP and that inhibition of PKMz with a peptide inhibitor (ZIP) can reverse established LTP. This session will focus on the hypothesis that PKMz plays a crucial role in maintaining chronic pain states. The findings presented will introduce new concepts concerning the molecular events that underlie pain chronification drawing remarkable parallels to memory processes in other CNS structures.
Theodore Price PhD, University of Arizona School of Medicine "Spinal PKMz maintains latent nociceptive sensitization"
Latent nociceptive hypersensitivity is thought to be an important aspect of pain chronification; however, the mechanisms that maintain this latent sensitization are not known. We have used a model wherein interleukin 6 (IL-6) is injected into the hindpaw, causing allodynia lasting for 3 days, and prostaglandin E2 (PGE2) is injected into the same hindpaw on day 6 after injection of IL-6 or vehicle. This subsequent PGE2 injection causes a long-lasting allodynia only in mice that have received previous IL-6 injections, termed latent sensitization. We demonstrate that inhibition of PKMz in the spinal cord, on day 4 post IL-6 injection, a time when mice are no longer allodynic, completely reverses latent sensitization to PGE2. This finding strongly suggests that PKMz in the spinal cord is required to maintain latent sensitization. Moreover, these findings support a model wherein central sensitization is maintained by PKMz even in the absence of any overt signs of allodynia or hyperalgesia.
Frank Porreca PhD, University of Arizona School of Medicine "PKMz maintains aversiveness of chronic neuropathic pain"
Neuropathic pain patients suffer from chronic pain that is often "spontaneous" or "stimulus-independent." Such pain may result from spontaneous discharge in primary afferent nociceptors in injured peripheral nerves. Human studies show that the rostral anterior cingulate cortex (rACC) mediates the negative affective component of acute pain. We have explored the possibility that the rACC integrates the aversive component of chronic spontaneous pain arising from nerve injury and that such pain is maintained by PKMz. We have used the principle of negative reinforcement to investigate mechanisms underlying the aversiveness of spontaneous pain driven from injured nerves. Our data indicate that spontaneous pain arising from injured nerve fibers produces a tonic aversive state that is mediated within the rACC in part through the activity of PKMz.
9:00am-10:30am: "RNA regulation in the nervous system"
Mechanisms utilizing coding and non-coding RNAs have been demonstrated to play increasingly important roles in all areas of biology, including the organization and function of the nervous system. For example, the control of mRNA transport, localization, stability, splicing and translation confers upon tissues the ability to alter protein levels locally and thus provide an additional critical layer of gene expression regulation. In addition, non-coding RNAs such as miRNAs have been shown to contribute to the stability and translation regulation of mRNAs and their cognate proteins. Such mechanisms have been shown to be critical in the nervous system for synaptic development and plasticity and more recently, for axon guidance and neural stem cell proliferation and differentiation. The goal of the proposed session is to highlight recent developments in the field of RNA based mechanisms in the nervous system.
Dr. Fen-Biao Gao , "MicroRNA Functions in Neuronal Development and Disease"
MicroRNAs (miRNAs) are small noncoding RNAs that regulate multiple developmental processes mostly through imperfect base-paring with specific sequences located mostly in the 3' untranslated regions (UTRs). A number of miRNAs play critical roles in neuronal development and function, including miR-9, a miRNA specifically expressed in the mammalian nervous system and 100% conserved at the nucleotide level among many species. In this talk, I will discuss diverse functions of miR-9 in different aspects of neuronal development and its potential misregulation in neurological diseases.
Dr. Jeffrey Twiss, "Local protein synthesis in axon growth and regeneration"
Several lines of evidence suggest that mRNAs are present in mature PNS axons, likely present in a stored state. This talk will focus on mechanisms underlying localized protein synthesis, which has been demonstrated in both developing and regenerating axons.
Dr. Stephanie Ceman, "Unraveling translation regulation by the Fragile X Mental Retardation Protein FMRP"
The fragile X mental retardation protein FMRP is required for normal cognition: when it is absent, the most common form of inherited mental retardation, fragile X syndrome results. Thus, FMRP is a molecular entry point for understanding normal neuronal function. FMRP is an RNA binding protein that binds ~4% of brain mRNAs and regulates their translation—either enhancing or suppressing translation by an unknown mechanism. Many of the mRNAs that bind FMRP have been identified; however, it is still unknown how FMRP regulates their translation. FMRP is both an activator and suppressor of translation (Brown, 2001). FMRP binds the 5' UnTranslated Region (5' UTR) of the achaete-scute mRNA to enhance its expression (Fahling, 2009). In contrast, FMRP binds the 3'UTR of the NMDA receptor subunit NR2A mRNA to suppress its translation (Edbauer, 2010). Our long-term goal is to uncover the mechanism of FMRP-mediated translation regulation. To gain insight into this question, we used mass spectrometry to identify the proteins associated with FMRP and found the putative RNA helicase MOV10. Like FMRP, MOV10 has recently been shown to be important for translation regulation in neurons (Banerjee et al. 2009). We reproduced the observation that FMRP enhances translation of the achaete-scute mRNA by binding its 5' UTR. Further, using siRNAs to eliminate MOV10, we show that MOV10 is required for FMRP-mediated translation upregulation. Our hypothesis is that MOV10 regulates translation of FMRP-bound mRNAs by unwinding duplexes in the RNA.
Daniela C Zarnescu, PhD (Chair), "Fragile X Protein Controls Neural Stem Cell Proliferation in the Drosophila Brain"
Fragile X Syndrome (FXS) is the most common form of inherited mental retardation and is caused by loss of function for FMRP, an RNA-binding protein thought to regulate synaptic plasticity by controlling the localization and translation of specific mRNAs. To determine whether FMRP is also required for proliferation during brain development we examined the distribution of cell cycle markers in dFmr1 brains compared to wild-type throughout larval development. Our results indicate that loss of dFmr1 leads to a significant increase in the number of mitotic neuroblasts and BrdU incorporation in the brain, consistent with the notion that FMRP controls proliferation during neurogenesis. Developmental studies suggest that FMRP also inhibits neuroblast exit from quiescence in early larval brains, as indicated by misexpression of Cyclin E. To determine the role of FMRP in neuroblast division and differentiation we used Mosaic Analysis with a Repressible Marker (MARCM) approaches in the developing larval brain and found that single dFmr1 neuroblasts generate significantly more neurons than controls. Our results demonstrate that FMRP is required during brain development to control the timing and proliferative capacity of neuroblasts as well as neuron production, which may provide insights into the autistic component of FXS. In this talk I will present new evidence that FMRP controls neural stem cell division using both cell autonomous and non-cell autonomous mechanisms involving glia.
10:30am-11:30pm: "Brain Tumor: Preclinical and clinical studies of the effects of vascular targeting agents on the blood-brain barrier and brain tumor vasculature"
Leslie L. Muldoon, PhD, Basic Studies
Edward A. Neuwelt, MD, Clinical Targeting
Agents that target tumor vasculature are gaining use as therapeutics for brain tumors. We used dynamic magnetic resonance imaging (MRI) to evaluate vascular characteristics in rat brain tumor models and in patients with brain tumors and CNS lesions, and to assess the impact of monoclonal antibodies targeting blood vessels.
For preclinical studies, female nude rats received intracerebral implantation of human tumor cells, including small cell lung carcinoma, breast carcinoma, and glioma. Rats were untreated or treated with intetumumab, targeting aV integrins, or bevacizumab, targeting vascular endothelial growth factor (VEGF). Serial dynamic MRI at 12T with the ultrasmall superparamagnetic iron oxide nanoparticle ferumoxytol was used to measure tumor relative cerebral blood volume (rCBV) and vascular permeability. We found that bevacizumab decreased rCBV, vessel permeability, and histological blood vessel staining, while intetumumab increased all measures. The diametrically opposite effects of these vascular targeting agents may have implications for chemotherapy delivery and efficacy in brain tumor patients.
For clinical studies, the utility of dynamic MRI with ferumoxytol nanoparticles has been investigated in six institutional review board - approved imaging research protocols. Studies include development of dynamic MRI techniques, diagnosis of pseudoprogression after radio-chemotherapy in glioblastoma, characterization of inflammation in brain tumors and CNS lesions, and assessment of the effects of vascular targeting with bevacizumab. We have found ferumoxytol to be well tolerated and provides complimentary information to standard gadolinium-based contrast agents. We hypothesize that dynamic MRI with ferumoxytol important information about fundamental aspects of brain and tumor vasculature that will improve diagnosis and provide better and earlier demonstration of tumor response to vascular-targeted treatments.
11:30am-12:30pm: Modulation of the Blood-Brain Barrier by Pathophysiological Stressors
The blood-brain barrier (BBB) is the regulated interface between the systemic circulation and the CNS. The anatomical correlate of the BBB is the cerebral microvascular endothelium, which, together with astrocytes, pericytes, neurons, and the extracellular matrix, constitute a "neurovascular unit" that is essential for maintenance of CNS homeostasis. Previous studies have demonstrated that the BBB can be dramatically altered in response to pathophysiological stressors (i.e., inflammation, pain, viral infection, stroke, traumatic brain injury); however, the biological mechanisms involved in these discrete BBB changes are just beginning to be investigated. A thorough understanding of how the BBB may be affected by various factors holds significant promise for the prevention and treatment of various diseases.
This symposium will focus on the most recent developments in the study of mechanisms of pathophysiological disruption of the BBB. Regulation of various aspects of the BBB (i.e., tight junction protein complexes, transporters, extracellular matrix) will be reviewed to demonstrate how the BBB is modulated by disease. Translational aspects of each study and future prospects will also be discussed.
Paula Dore-Duffy
Patrick Ronaldson
Richard Milner, "A Role for Fibronectin in Cerebral Angiogenesis"
The extracellular matrix (ECM) is an important influence on angiogenesis and vascular remodeling. We have shown that angiogenic vessels in the developing central nervous system (CNS) express high levels of fibronectin and the fibronectin receptor a5b1 integrin. In keeping with an angiogenic role for fibronectin in other systems, this implies that fibronectin may provide an important angiogenic drive in the CNS. To investigate whether this mechanism also applies to the adult CNS, we examined these events in a mouse model of cerebral hypoxia, in which mice are exposed to 8% O2. Over a 2-week period, this results in a robust increase (50%) in vessel density in the brains of these mice. Immunohistochemistry and western blot revealed that hypoxia strongly induced fibronectin and brain endothelial cell (BEC) expression of the a5b1 and avb3 integrins. To directly test whether these BEC integrins are required for cerebral angiogenesis, the hypoxic response was examined in transgenic mice deficient in either the a5 or b3 integrins. This revealed that while the avb3 integrin is not essential for the angiogenic response, the a5b1 integrin plays an important role in driving BEC proliferation. In current experiments, we are generating a5/b3 double-KO mice to examine whether the hypoxic-angiogenic response is “flat-lined” in the absence of both BEC fibronectin receptors, or whether other redundancy or compensation exits in this response.
Gregory Bix
LUNCH
Posters will be viewed in the vendor exhibit area. Afternoons are available for information interaction and the many attractions in Tucson.
Poster Presentations:
Celebrating the Three-Century Anniversary of Systematic Ablation of the Brain in Experimental Animals by Pourfour du Petit
Authors; Lawrence Kruger, Dept. of Neurobiology, University of California, Los Angeles (UCLA), Los Angeles CA 90095 and Larry W. Swanson, Dept. of Biological Sciences, University of Southern California (USC) Los Angeles, CA 90089
The publication in Namur (Belgium) in 1710 of the remarkable pioneering efforts of French military surgeon Francois Pourfour du Petit constitutes an obscure and largely forgotten landmark in neuroscience history. He made original observations of specific neurological consequences of brain injuries in wounded soldiers by postmortem examination and dissection of the brain. He then innovated methods for ablating different sectors of the cerebrum and cerebellum of dogs. His report depicts the first correct account of the pyramidal decussation and the explanation of contralateral paralysis and describes findings indicating specific features of motor and sensory functional localization in the cerebrum and cerebellum in animals- extraordinary early “retrograde translational” experiments derived from observations of human brain injury.
Neu2000 Exerts Potent Anti-Oxidant Effects on Rat Spinal Cord Mitochondria in situ and in vitro.
Authors: Visavadiya, NP, McEwen, ML, Pandya, JD, Sullivan, PG, Gwag, BJ, and Springer, JE
Secondary injury following traumatic spinal cord injury (SCI) involves a number a highly complex pathophysiological events. Oxidative damage has long been recognized as a contributor to secondary injury and numerous strategies focusing on anti-oxidant therapies have been a major area of research interest. Neu2000 is a novel derivative of acetylsalicylic acid and sulfasalazine with potent free radical scavenging properties. Mitochondria are a major source of free radicals and we have previously shown that mitochondrial function is compromised at acute times following SCI. Therefore, we pursued two sets of studies to examine the ability of Neu2000 to reduce free radical-mediated oxidative damage and improve mitochondrial function at acute times following SCI. In the first set of studies, animals received a moderate SCI followed by Neu2000 treatment (20mg/kg) at one hour following injury. Mitochondria were isolated at 24 hours after injury and measures of mitochondrial respiration/bioenergetics obtained. SCI resulted in a significant loss in mitochondrial respiratory control ratios as well as Complex I, Complex II, and State III dependent oxygen consumption. However, treatment with NEU2000 resulted in a significant “normalization” on mitochondrial measures to near control values. In a second set of studies, the potency of Neu2000 on reducing free radicals and oxidative damage generated in vitro in mitochondria obtained from uninjured spinal cords. The results of these in vitro studies demonstrated that 1) Neu2000 is a potent inhibitor of reactive oxygen/ nitrogen species, and 2) as a consequence, Neu2000 significantly reduced the appearance of lipid peroxidation and protein carbonyl products. Collectively, these studies provide compelling evidence that Neu2000 exerts potent anti-oxidant effects in mitochondria challenged by SCI or exogenous production of free radicals. This study was supported by KSCHIRT grant 7-23 (JES) and a grant from the Craig H. Neilsen Foundation (MLM).
Aberrant integration of postnatally generated granule cells is sufficient to cause epilepsy
Raymund YK Pun, Katherine D Holland, David A Richards, Juli D Uhl, Christian Faulkner, Hulian Yin, Stefanie L Bronson, Brian L Murphy, and Steve C Danzer
Aberrant integration of hippocampal dentate granule cells has been hypothesized to underlie the development of temporal lobe epilepsy. Here, we tested this hypothesis by developing a conditional, inducible transgenic mouse model to selectively delete PTEN from a subset of granule cells, while leaving the rest of the brain largely unaffected. Deletion of PTEN leads to hyperactivation of the mTOR pathway, producing abnormal granule cells which are morphologically similar to those seen in epilepsy. Animals in which PTEN was deleted from 15-20% of the granule cell population developed spontaneous seizures within four weeks. These findings demonstrate that a relatively small population of abnormal hippocampal granule cells is capable of causing epilepsy.
Last Updated 3/14/11