| dc.description.abstract |
<p>Epilepsy is a syndrome that affects about 65 million people around the world. About
150,000 new cases of epilepsy are reported in the United States every year. Temporal
lobe epilepsy (TLE) is the most common form of human epilepsy. It is a chronic neurological
disorder characterized by recurrent seizures that are devastating due to a lack of
effective treatment. TLE is resistant to anticonvulsants and one-third of patients
diagnosed with TLE are refractory to medication. </p><p>Excessive activation of tropomyosin
receptor kinase B (TrkB) promotes TLE. The importance of phospholipase Cγ1 (PLCγ1)
as a major downstream signaling effector of TrkB was first identified by the McNamara
lab at Duke. Thus, selective inhibition of the PLCγ1-TrkB interaction constitutes
a promising avenue for new drugs.</p><p>As a proof-of-concept, the McNamara lab engineered
a novel 14-mer peptide pY816 that effectively inhibits epilepsy and prevents anxiety-like
behavior induced by continuous seizure activity (status epilepticus), in a dose- and
time-dependent manner. Despite their promising therapeutic effectiveness, the molecular
details of the engagement of these inhibitors with PLCγ1 have remained elusive. </p><p>In
this study, we propose x-ray crystallography and solution NMR studies to elucidate
the binding mode of the peptide to PLCγ1 tandem SH2 domains. This will ultimately
facilitate the development of novel therapeutics targeting the TrkB-PLCγ1 interaction.</p>
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