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Characterization of a TrkB-derived Phosphopeptide Inhibitor of PLCγ1

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Date
2018
Author
Tan, Chin Huat
Advisor
Zhou, Pei
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Abstract

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.

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.

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.

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.

Type
Master's thesis
Department
Biochemistry
Subject
Biochemistry
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https://hdl.handle.net/10161/16976
Citation
Tan, Chin Huat (2018). Characterization of a TrkB-derived Phosphopeptide Inhibitor of PLCγ1. Master's thesis, Duke University. Retrieved from https://hdl.handle.net/10161/16976.
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States License.

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