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Janice R. Naegele
 Professor
and
Chair
Ph.D. (neuroscience) Massachusetts Institute of Technology
Campus Extension: 3232
Room #: Hall-Atwater Labs 254
E-Mail: JNAEGELE@WESLEYAN.EDU
Programmed cell death and neurodegeneration in the mammalian
cerebral cortex and hippocampus; stem cell therapy for epilepsy;
STEP and control of seizures.
Current work in my laboratory examines how neuronal cell death
and neurogenesis are regulated in the embryonic and adult
mammalian brain. Our group studies these processes during normal
development, in developmental disorders, and in epilepsy. Our
focus is on both endogenous neural precursors in the fetal brain
and on mouse and human ES-derived neural stem cells.
Role of DNA repair in neuronal cell death in the cerebral cortex
and hippocampus. We study mice deficient in the
Non-homologous end-joining pathway (NHEJ), a mechanisms for DNA
double strand break (DSB) repair, to understand how DNA damage
triggers apoptosis. We showed that Ku70 is required for neuronal
survival, as neural stem cells make the transition to becoming
postmitotic neurons. NHEJ in developing neurons may serve to
repair DSBs incurred as young neuroblasts differentiate,
migrate, or establish synaptic connections. Current work is
identifying the sources of DSBs and signals, including Bax and
p53, that trigger cell death. We have also found a role for NHEJ
in maintenance of adult neural stem cells in the adult
subventricular zone and dentate gyrus, two regions of on-going
neurogenesis in the adult brain. We utilize a variety of
cutting-edge techniques, including in utero electroporation, RNA
interference, primary cell cultures, neurosphere cultures,
immunohistochemistry, and BrdU birthdating.
Epilepsy. In human mesial temporal lobe epilepsy (TLE) and in
rodent models of TLE, status epilepticus (a sustained seizure)
may trigger neurodegeneration in the hippocampus and related
limbic circuits, as well as mossy fiber sprouting and other
plastic changes. We have shown that DNA-PKcs deficient mice
exhibit an enhanced neurodegenerative response to kainic acid
induced seizures, suggesting that NHEJ protects mature neurons
from excitotoxic damage. We have also demonstrated that kainic
acid induced excitotoxic cell death activates the DNA repair
enzyme PARP within injured neurons. My lab uses several distinct
chemoconvulsant models of TLE (pilocarpine, kainic acid) to
study neuronal repair, neuroprotection and excitotoxic cell
death. Seizures are studied behaviorally using direct
observations, video recordings, and electroencephalography
(EEG). We have on-going collaborations with labs at Wesleyan,
Yale, and Ohio State for our epilepsy work.
ES-derived GABAergic neurons for neuronal repair and seizure
control. We have shown that intrahippocampal grafts of murine
and human ES cell-derived neural stem cells survive, migrate,
and integrate into the dentate gyrus of mice following kainic
acid-induced seizures. Currently, we making transplants into the
adult hippocampus of mice after status epilepticus to test
whether ES-derived neural stem cell grafts can limit or reduce
seizures. We aim to generate GABAergic precursors from mouse and
human ES cell lines for these studies.
Striatal Enriched Phosphatase (STEP), Seizure thresholds, and
Excitotoxcity. The mechanisms leading to recurrent seizures and
epilepsy are not well understood. Recent work in the lab has
identified increased seizure thresholds in mice deficient in
STEP, an important protein tyrosine phosphatase that regulates
NMDA receptors and extracellular regulated kinase (ERK). Both of
these proteins play critical roles in neuronal survival and
excitability. Studies are exploring the mechanisms for seizure
resistance in STEP knockout mice, hippocampal slices, and
neuronal cell cultures derived from the hippocampus of these
mice.
Our research on mouse and human embryonic stem cell-derived
therapies for epilepsy is funded by grants from the McKnight
Foundation (http://www.mcknight.org/neuroscience/),
the Andrew W. Mellon Foundation (http://www.mellon.org/),
the Connecticut Stem Cell Research Fund (PI: Laura Grabel), and
an undergraduate bioscience fellowship from The Connecticut
Business & Industry Association (CBIA) and CURE (Connecticut
United for Research Excellence) (http://www.curenet.org/index.php).
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