MARC 主機 00000nam a2200373 4500
001 AAI3685004
005 20151109142631.5
008 151109s2015 ||||||||s|||||||| ||eng d
020 9781321605334
035 (MiAaPQ)AAI3685004
040 MiAaPQ|cMiAaPQ
100 1 Li, Zhuting
245 10 Activity-dependent gene regulation in neurons: Energy
coupling and a novel biosensor
300 120 p
500 Source: Dissertation Abstracts International, Volume: 76-
07(E), Section: B
500 Advisers: Shelley J. Russek; Xue Han
502 Thesis (Ph.D.)--Boston University, 2015
520 Multiple brain disorders are associated with
hypoinhibition of neural circuits that are controlled by
inhibitory neurons using the neurotransmitter gamma-
aminobutyric acid (GABA). GABA activates type A receptors
(GABARs) to mediate the majority of inhibitory
neurotransmission and changes in GABAR subunit composition
have profound effects on brain function. In fact, down-
regulation of one of the three beta isoforms, beta1, is
associated with alcoholism, autism, epilepsy,
schizophrenia, and bipolar disorder. These conditions also
present with mitochondrial defects and metabolic
dysregulation
520 In the first Aim of my thesis, I ask whether the core
promoter of the human GABAR beta1 subunit gene (GABRB1 )
can be regulated by the same transcription factor, the
nuclear respiratory factor 1 (NRF-1) that controls
oxidative phosphorylation and mitochondrial biogenesis in
neurons. The ENCODE database of NRF-1 binding in human
embryonic stem cells was used to identify an interaction
of NRF-1 with GABRB1. Using a variety of approaches:
electro mobility shift, promoter/reporter luciferase
assays, gene silencing and bioinformatics, we demonstrate
that GABRB1 contains a canonical NRF-1 element responsible
for the majority of GABRB1 promoter- luciferase activity
in transfected primary neurons. Moreover, we show that
endogenous NRF-1 is responsible for a substantial amount
of luciferase activity in our studies. Altogether, our
results suggest GABRB1 is a target gene for NRF-1,
providing a possible link between mitochondria related
energy metabolism and transcriptional regulation of beta1-
containing GABARs in neurological disease
520 Synthesis of NRF-1 is regulated by the transcription
factor cAMP response element binding protein (CREB), an
important memory molecule implicated in multiple brain
disorders. The second Aim of my thesis was to develop a
molecular sensor that can be used in living neurons to
signal the presence of CREB dependent gene regulation. We
employ a split complement bioluminescent sensor to monitor
interaction of protein surfaces that link CREB with its co
-factor CBP and demonstrate that it can detect activation
of CREB via its serine 133 phosphorylation site and
activation through an undiscovered mechanism. We also
show that this sensor can be used to monitor BDNF
signaling providing the foundation for its future use in
in vivo models of disease where BDNF is implicated
590 School code: 0017
650 4 Neurosciences
650 4 Biomedical engineering
650 4 Pharmacology
690 0317
690 0541
690 0419
710 2 Boston University.|bBiomedical Engineering
773 0 |tDissertation Abstracts International|g76-07B(E)
856 40 |uhttps://pqdd.sinica.edu.tw/twdaoapp/servlet/
advanced?query=3685004
912 PQDT
