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Research Studies
Cerebrovascular/ Stroke

The Department of Neurological Surgery is currently conducting the following studies in Cerebrovascular/ Stroke:


Mechanisms of Neuroprotection by Histone Deacetylase Inhibition

Principal Investigator: Richard Morrison, PhD
Funded By: National Institutes of Health (NIH)

The tumor suppressor p53 is an important apoptosis regulator in acute and chronic neurological insults and neurodegenerative disorders. However, the downstream molecular consequences of p53 activation in neurons still remain obscure. Our proteomic analyses demonstrate that DNA damage-induced neuronal apoptosis involves a p53-dependent increase in the expression of proteins that comprise histone deacetylase (HDAC) complexes.

These data suggest p53 might promote neuronal dysfunction/cell death by activating histone deacetylase activity. Our preliminary studies demonstrate that histone deacetylase inhibitors protect against p53-mediated cell death. In contrast HDAC activity is elevated in cancer cells, and HDAC inhibition actually induces p53-dependent cell death. In the present application, based on this novel finding of the neuron-specific mode of HDAC inhibitor actions, we propose to test the hypothesis that p53-mediated cell death signaling in neurons is dependent on histone deacetylase activity by examining how HDAC inhibitors block neuronal cell death.

We will specifically:

  1. Determine if HDAC inhibitors selectively protect neurons from p53-mediated cell death
  2. Determine if HDAC inhibitors directly block p53 activation and/or transcriptional activity required for p53-dependent cell death in neurons
  3. Determine if HDAC inhibitors prevent p53-dependent changes in mitochondrial integrity
  4. Characterize global changes in protein expression and protein acetylation induced by HDAC inhibition
  5. Determine if HDAC inhibitors block p53-dependent cell death in vivo

The aims of this proposal will help us better understand the molecular sites and mechanism of HDAC inhibitor action, which will enhance the utility of these inhibitors as therapeutic agents for neurological diseases and injury.

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Mechanisms of Neuroprotection Mediated by Histone Deacetylase Inhibition in Ischemic Injury

Principal Investigator: Richard Morrison, PhD
Funded By: American Heart Association

Finding interventions that improve outcome from ischemic stroke has proved to be challenging and current treatment is limited to thrombolysis, aspirin, and management in a stroke unit. An ideal stroke therapeutic would minimize damage to mature neurons and also maximize the generation of new neurons from endogenous progenitors. Recent findings in vitro and in animal models of stroke suggest that histone deacetylase (HDAC) inhibitors meet these criteria.

Administration of broad spectrum HDAC inhibitors protects isolated neurons and white matter from stress, results in improved histologic and functional outcomes following cerebral ischemia, and appears to drive "neuronal" differentiation of multipotent adult neural progenitor cells. The mechanism by which HDAC inhibition confers neuronal protection in response to ischemic injury is not understood. In the present application, based on our novel finding that HDAC inhibitors block p53-mediated cell death, we propose to test the hypothesis that HDAC inhibition protects neurons from ischemia-induced death by suppressing p53-mediated cell death signaling in neurons and maintaining mitochondrial integrity.

We will specifically:

  1. Determine if the most specific class I HDAC inhibitor available, MS-275, protects neurons from cell death in response to ischemic injury induced by middle cerebral artery occlusion
  2. Determine if MS-275 directly blocks p53 expression and/or transcriptional activity
  3. Determine if MS-275 prevents changes in mitochondrial integrity which could occur independently of p53
  4. Determine if MS-275 suppresses the expression of autophagy

The aims of this proposal will help us to better understand the molecular sites and mechanism of HDAC inhibitor action in stroke, which will enhance the utility of these inhibitors as therapeutic agents for neurological diseases and injury.

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Mechanisms of Neuronal Survival

Principal Investigator: Richard Morrison, PhD
Funded By: National Institutes of Health (NIH)

The p53 tumor suppressor gene is a sequence-specific transcription factor that activates the expression of genes engaged in promoting growth arrest or cell death in response to genotoxic stress. A role forp53-related modulation of neuronal viability has been suggested by the finding that p53 expression is elevated in damaged neurons in acute models of injury such as ischemia and epilepsy and in brain tissue samples derived from patients with chronic neurodegenerative diseases. Moreover, the absence of p53 has been shown to protect neurons from a wide variety of acute toxic insults consistent with the hypothesis from our previous applications that p53 expression regulates neuronal viability after injury. Our long-range objective is to assess the consequences of p53 gene expression in the CNS. However, the downstream molecular consequences of p53 activation in neurons remain obscure.

Our proteomic analyses demonstrate that p53 is associated with injury-induced alterations in the expression of proteins that reside in or associate with the mitochondria. Mitochondrial dysfunction is a hallmark of stress-induced neuronal toxicity. Therefore, in the present research, we are testing the hypothesis that p53 promotes neuronal cell death by altering the expression or distribution of proteins that regulate mitochondrial integrity.

Our research goals are to:

  1. Determine if the p53 protein promotes a loss of mitochondrial integrity and changes in cytoskeletal organization through the induction and mitochondrial translocation of cofilin
  2. Determine if the p53 protein promotes mitochondrial dysfunction and neuronal death by regulating the N-BAK protein
  3. Determine if dynamin-related protein-1 (Drp1) promotes mitochondrial dysfunction and neuronal death
  4. Identify p53-dependent changes in the mitochondrial proteome

These studies will help elucidate the mechanism by which p53 regulates neuronal survival and activity in response to injury and neurologic disease.

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Mechanisms Underlying the Benefits of Progesterone for Stroke

Principal Investigator: Sean Murphy, PhD
Funded By: American Heart Association (AHA)

Using experimental animal models of stroke (permanent and transient middle cerebral artery occlusion in the mouse) we have identified progesterone administration following injury as being highly beneficial to both anatomic and also functional outcomes. Our published and preliminary studies suggest that the drug suppresses specific aspects of the inflammatory response.

The benefits of progesterone appear to extend beyond a reduction in cortical lesion volume and the positive effects are evident 21 days later, both in terms of neuronal complement in vulnerable brain regions and also in the performance of mice on motor and cognitive tasks. Thus far, progesterone satisfies many of the stringent criteria proposed for preclinical stroke trials. Furthermore, the outcomes of a recent Phase II clinical trial of progesterone use for acute traumatic brain injury (ProTECT) are very promising.

The administration of progesterone itself may have clinical limitations because of potential interactions with estrogen signaling pathways. A better understanding of the mode of action of this drug in experimental stroke models could facilitate development of directed therapeutics with better clinical potential, and the specific aims of the current application are designed to uncover the mechanisms underlying the functional benefits that progesterone confers.

First, we shall determine whether it is progesterone itself and/or a metabolite (allopregnanolone) that suppresses expression of specific genes associated with the inflammatory response, using in vitro (cell culture) and in vivo approaches (progesterone receptor knockout mice). Secondly, we shall define the cellular consequences of progesterone/allopregnanolone administration in vivo, both in terms of acute neuroprotection and also the effects of these drugs on the process of neurogenesis that is stimulated by ischemic injury to the brain (neurorestoration).

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Histone Deacteylases: Therapeutic Targets for Functional Restoration After Stroke

Principal Investigator: Sean Murphy, PhD
Funded By: National Institutes of Health (NIH)

Stroke is the major cause of adult disability, the third most common cause of death, and consumes a significant proportion of national health resources. At six months, two-thirds of patients are either dead or dependent upon others. Finding interventions that improve outcome has proved to be challenging and the treatment for ischemic stroke is limited to thrombolysis, aspirin, and management in a stroke unit. While aspirin has wide utility but modest efficacy, and alteplase the converse, anticoagulation and targeted neuroprotection have so far failed.

The ideal stroke therapeutic would be one that not only acutely protects existing neurons and white matter but also amplifies and maximizes "neuronogenesis", the restorative response of the brain to injury. Our recent findings with the pan-histone deacetylase (HDAC) inhibitor, vorinostat (SAHA), suggest that administration of this drug coincident with experimental stroke (middle cerebral artery occlusion, MCAO) results in improved histologic outcome. This acute effect of HDAC inhibition is a result of protection of the existing complement of fully differentiated (post-mitotic) neurons.

In addition, we have observed in vitro that vorinostat can drive the "neuronal" differentiation of multipotent adult neural progenitor cells. These data suggest that selective HDAC inhibitors could be ideal drugs for the treatment of stroke.

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A Randomized Trial of Unruptured Brain Arteriovenous Malformations

Principal Investigator: Laligam Sekhar, MD
Funded By: NIH Sponsored Multi-center clinical trial

ARUBA, a randomized trial of unruptured brain arteriovenous malformations, is a project formulated by the staff of the Doris & Stanley Tananbaum Stroke Center, Neurological Institute and the InCHOIR Clinical Trial Center, both of the Columbia University Medical Center.

Current treatment of brain arteriovenous malformations (BAVMs) is varied and includes endovascular procedures, neurosurgery, and radiotherapy. All of these treatments are administered on the assumption that they will decrease the risk of subsequent hemorrhage and lead to better long-term outcomes. Recent data from the literature, including that from Columbia University's Neurological Institute, comparing initial presentation and outcome for those presenting ruptured or unruptured, have raised the possibility that interventional treatment in patients with unruptured BAVMs may be detrimental compared with natural history, but no definitive information exists on the patient population overall nor on the outcomes estimated by either the commonly-used Spetzler-Martin Scale or the Neurological Institute Hemorrhage Risk Profile.

The goal of the project is to test the null hypothesis that treatment, by means of interventional procedures, surgery, or radiotherapy offers no difference in the risk of death or symptomatic stroke, and no better functional outcome than does conservative management at five years from discovery of an unruptured brain arteriovenous malformation (BAVM).

Adult patients discovered with a BAVM not having bled, as documented by any of several imaging techniques (angiography not required if CT or MR satisfactorily demonstrate the lesion) and whose lesion appears feasible for treatment, will be asked to participate in the randomization process. The alternative hypothesis is that death or symptomatic stroke will differ by an absolute magnitude of at least 10% over five years for the non-interventional versus the interventional arms.

A secondary hypothesis is that there will be no difference in functional outcome comparing the two arms as assessed by the Rankin scale and the European Quality of Life Scale will be used for outcome assessment. A five-year period of follow-up for outcome is selected for comparison, based on this time frame within which most of the literature is represented.

To complement the information derived from assessing functional capacity, the trial formally measures the quality of life experienced by patients in both treatment arms. Quality of life is assessed in a longitudinal fashion using standard scales including a measure of general health status (SF-36) and a measure of patient preference (European Quality of Life Scale). The economic analysis, which is limited to U.S. centers, measures the direct cost of health care, including the cost of the initial assessment, all follow-up imaging studies and all hospitalizations for patients in both treatment arms. In addition to acute care facilities, the study captures the use of rehabilitative and long-term care facilities for stroke events in patients from both arms of the study.

To date, more than one hundred major centers in the Americas, Europe and Australia have signed up to participate in this randomized trial.

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Published Research Articles

View complete lists of current research publications by faculty from the Department of Neurological Surgery.

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Featured Faculty:

Franck Kalume, PhD

Dr. Kalume investigates a form of epilepsy called Dravet Syndrome, as well as the mechanism that allows the ketogenic high-fat diet to suppress seizures.

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