I actively mentor residents, postdoctoral fellows and junior faculty. I have trained over 25 postdoctoral fellows in my laboratory, and over 30 undergraduate and graduate students since starting my laboratory in 1987. The vast majority the postdoctoral trainees are now in faculty positions at competitive academic medical institutions and universities. Over 90% of these trainees obtained independent funding from NIH or private foundations while in my laboratory, including 3 KO8 awardees of whom I served as primary mentor. I am currently the PI on the R25 for Resident training in the Neurosciences at Children’s Hospital and the Beth Israel Deaconess residency programs.
As Director of Epilepsy Research as well as Director of Translational Neuroscience, I mentor junior faculty on a wide range of topics, and in some instances serve as research supervisor for training grants. We have established a successful seminar series for both programs, and invite both external as well as internal speakers to encourage dialog and new collaborations.
With respect to teaching leadership I have been involved as an organizer and speaker at a national, international, and regional level in educational symposia furthering the understanding of the role of brain development in the mechanism of diseases such as stroke and epilepsy, including planning and participating in such activities for the National Institutes of Heath, Society for Neuroscience, American Epilepsy Society, Workshop on Epilepsy Research, and the National Academy of Sciences/Society for Neuroscience African Initiative. I served as Chair of the Annual Meeting Committee and Council of Education for the American Epilepsy Society, and oversaw the process for ACCME accreditation, which was achieved at the exemplary level. I also served as Chair of the Program Committee for the Society for Neuroscience, and now serve on Council.
Recent activities with the Neurology residents at the Children’s Hospital and the Brigham and Women’s Hospital includes training on hypothesis generation, grant writing. In addition, I am running an Epilepsy Treatment Algorithm project in development for both hospitals, in order to streamline our management of first and second seizure patients. This will be QI as well as CER activity for the departments.
In my capacity as Director of Epilepsy Research and Translational Neuroscience, as well as the natural extension of my own translational research, I have become involved in clinical research projects.
1) FDA- approved Phase I/II trial of bumetanide in neonatal seizures. I serve as FDA sponsor, and this project has emerged directly from basic research performed in my laboratory as well as Dr. Kevin Staley, and others. The trial was funded by an NIH RO1 grant (2010-2015), with the PI being Dr. Janet Soul, and Drs. Jensen and Staley are among the Co-PIs. The trial is now actively recruiting patients
2) Examination of cognitive and psychological comorbidities in pediatric epilepsies. In a first study, a team of from the Psychiatry department (J Gonzalez, MD and K Boyer, PhD) and Neurology (M Takeoka, MD) are examing the incidence of depression and learning disabilities in children with complex partial seizures and childhood absence epilepsy. In a related study, we are examining the incidence of learning disabilities in benign rolandic epilepsy in children, and the extent to it is related to the frequency of ictal and interictal EEG abnormalities.
3) Examination of abnormal synaptic transmission in human tissue removed from patients with refractory epilepsy or encephalitis. This is an interdisciplinary group and investigative only but has developed a centralized multi-PI IRB with universal consent form to improve availability of human tissue for experimental study and genetics.
The primary focus of my research is to investigate pathophysiological mechanisms of epilepsy and stroke, and secondary effects on synaptic plasticity. A secondary goal is to elucidate age-dependent differences in such mechanisms, and to examine the interactions between brain development, excitotoxic brain injury, epilepsy and cognition. Neurotransmitter receptors are developmentally regulated, and we have specifically demonstrated critical roles of these receptors, as well as their upstream modulators and downstream effectors, in neuronal and glial cells that are unique to the immature, implying age-specific disease mechanisms. The overall aim is to develop new targets based on novel mechanisms for the treatment of epilepsy, stroke, and autism.
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Summary of major research findings:
1. Establishment of in vivo and in vitro rodent models of neonatal seizures and perinatal hypoxic/ischemic cerebral injury for examination of cellular and molecular factors influencing age-specific susceptibility, epileptogenicity, and cellular injury.
2. Demonstration that calcium-permeable AMPA receptors are constitutively expressed on neurons and glia in developing rodent and human hippocampus and neocortex, and that these are critical to the mechanisms of seizures and ischemic injury in the developing brain.
3. First demonstration that AMPA receptor antagonists selectively block seizures in the immature brain, but not in the adult. Additional demonstration that the clinically available drugs topiramate and talampanel attenuate AMPA receptor currents and suppress neonatal seizures and stroke, including periventricular leukomalacia, in rat models.
4. Elucidation of novel calcium-mediated signaling pathways downstream from the AMPA receptor that play critical roles in the pathogenesis of epilepsy in the immature brain, and preclinical efficacy of preventative or rescue treatment in rodent models. Specific pathways include those mediated by early post-translational changes to glutamate and GABA receptors that increase synaptic excitability. First demonstration that AMPA receptor antagonists including NBQX, topiramate and talampanel can reverse these changes when administered as post-seizure treatment, and prevent long term changes.
5. Identification of novel phosphorylation sites Ser 831 and Ser 845 on the GluR1 subunit of the AMPA receptor that are required for the epileptogenic effect of early life seizures, suggesting a novel mechanism for epileptogenesis.
6. Development of novel antiepileptic and neuroprotective strategies that are permissive of neuronal plasticity and long term potentiation. These include the NMDA receptor redox site modulator pyrroloquinoline quinone, and the use-dependent, uncompetitive NMDA blocker memantine as highly protective in vivo and in vitro stroke models, without significant neurocognitive effects.
7. Identified parallel patterns of relative underexpression of the KCC2 chloride transporter versus NKCC1 transporter in human and rodent perinatal cortex during developmental period when GABA receptor agonists are ineffective as antiepileptic agents. This result is the first to strongly implicate the presence of depolarizing GABA receptors in human neonates. This date provided the preclinical target validation that was critical for translation of the use of the NKCC1 inhibitor bumetanide in an FDA approved NIH-funded ongoing clinical trial at CHB and Partners – Phase I/II safety PK trial in neonatal seizures.
8. Elucidation of abnormal patterns of glutamate and GABA receptors,in human tissue from malformations of cortical development, such as Tuberous Sclerosis, and that these changes are associated with epileptic foci. These results are presently under evaluation with respect to the generation of new clinical treatment trials.
9. Demonstration of convergence of signaling deficits in early life seizures and autism. Alterations in canonical autism-related pathways, including mTOR, FMRP and MeCP2, occur secondary to seizures in the developing brain.
In summary, the emphasis of this translational research program is to identify age-specific mechanisms of brain injury at the cellular level using a variety of in vivo and in vitro techniques, and to use this information to explore and devise experimental therapeutic strategies with clinical potential. Several therapeutic strategies developed in the laboratory are being considered for clinical development. We have established IRBs that have created a repository of human tissue from surgical specimens and autopsy material, and routinely obtain brain tissue directly from surgery for electrophysiological investigation.
Jantzie Lauren L, Talos Delia M, Jackson Michele C, Park Hyun-Kyung, Graham Dionne A, Lechpammer Mirna, Folkerth Rebecca D, Volpe Joseph J, Jensen Frances E: Developmental Expression of N-Methyl-D-Aspartate (NMDA) Receptor Subunits in Human White and Gray Matter: Potential Mechanism of Increased Vulnerability in the Immature Brain. Cerebral cortex (New York, N.Y. : 1991) Sep 2013.
Engel J Jr, Pitkänen A, Loeb JA, Edward Dudek F, Bertram EH 3rd, Cole AJ, Moshé SL, Wiebe S, Jensen FE, Mody I, Nehlig A, Vezzani A.: Epilepsy Biomarkers. Epilepsia August 2013.
Pitkänen Asla, Nehlig Astrid, Brooks-Kayal Amy R, Dudek F Edward, Friedman Daniel, Galanopoulou Aristea S, Jensen Frances E, Kaminski Rafal M, Kapur Jaideep, Klitgaard Henrik, Löscher Wolfgang, Mody Istvan, Schmidt Dieter: Issues related to development of antiepileptogenic therapies. Epilepsia 54 Suppl 4: 35-43, Aug 2013.
Brooks-Kayal Amy R, Bath Kevin G, Berg Anne T, Galanopoulou Aristea S, Holmes Gregory L, Jensen Frances E, Kanner Andres M, O'Brien Terence J, Whittemore Vicky H, Winawer Melodie R, Patel Manisha, Scharfman Helen E: Issues related to symptomatic and disease-modifying treatments affecting cognitive and neuropsychiatric comorbidities of epilepsy. Epilepsia 54 Suppl 4: 44-60, Aug 2013.
Wintermark Pia, Lechpammer Mirna, Warfield Simon K, Kosaras Bela, Takeoka Masanori, Poduri Annapurna, Madsen Joseph R, Bergin Ann M, Whalen Stephen, Jensen Frances E: Perfusion Imaging of Focal Cortical Dysplasia Using Arterial Spin Labeling: Correlation With Histopathological Vascular Density. Journal of child neurology May 2013.
Ryan T. Cleary, Hongyu Sun, Thanhthao Huynh, Simon M. Manning, Yijun Li, Alexander Rotenberg, Delia M. Talos, Kristopher T. Kahle, Michele Jackson, Sanjay N. Rakhade, Gerard Berry, Frances E. Jensen: Bumetanide Enhances Phenobarbital Efficacy in a Rat Model of Hypoxic Neonatal Seizures. PLOS ONE Page: 10.1371/journal.pone.0057148, March 2013.
Jacobs Margaret, Jensen Frances E: Introduction to institute of medicine report: epilepsy across the spectrum: promoting health and understanding. Epilepsy currents / American Epilepsy Society 12(6): 243-4, Nov 2012.
Kowbow K, Auvin S, Jensen F, Loscher W, Mody I, Potschka H, Prince D, Sierra A, Simonato M, Pitkanen A, Nehlig A, Rho JM: Finding a better drug for epilepsy: Antiepileptogenesis Targets. Epilepsia November 2012.
Zhou C, Lippman Bell JJ, Sun H, Jensen FE: Learning Through Silence: Amping up Cognition After Neonatal Hypoxic Seizures Through AMPA Receptor Inhibition. Journal of Neuroscience September/October 2012.
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Last updated: 10/01/2015
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