| Summary: | 碩士 === 國立宜蘭大學 === 生物技術與動物科學系生物技術碩士班 === 107 === The definition of epigenetic regulation is the heritable changes in gene function and
phenotype that do not involve changes in the DNA sequence. The modification includes
acetylation, phosphorylation, methylation and ubiquitination especially acetylation
which is the most important modification of epigenetic regulation. Histone
acetyltransferase (HAT) can acetylate histones and non-histone proteins to facilitate the
chromatin structure release from the binding histones and increases gene
expression/transcription and the function of non-histone proteins. In contrast, histone
deacetylase (HDAC) can remove the acetyl groups on the histone/non-histone proteins.
The recent researches have showed that histone deacetylase inhibitors (HDACi) also
has the potential in treatment of the central nervous system diseases. However, the side
effects are often concerned after treating by HDACi. Therefore, developing a selective
HDACi might be reduce the toxicity and side effects. It’s has been showed that many
available class I HDACi cannot inhibit HDAC8, or they need higher dose to inhibit
HDAC8 because of the enzymatic pocket of HDAC8 may be different from the other
class I members. Thus, it worths to develop a selective HDAC8 inhibitor. In our study,
PCI-34051 is adopted as a positive control since it is the currently most effective and
selective HDAC8 inhibitor. In the past, our lab has screened a series of selective
HDAC8 inhibitors including compounds series A and F. Both of A2 and F3 have been
identified to have better effect on neural plasticity as well as to demonstrate their
capability in enhancement of learning and memory in animal models. The aim of the
study is to investigate the mechanism of the selective HDAC8 inhibitors on neural
plasticity and the effects of learning and memory in mice. The results show that in the
nucleus, A2 and F3 up-regulate the secretion of brain-derived neurotrophic factor
(BDNF) by up-regulating BDNF promoter IV, and acetylated tubulin assists BDNF
transport to the extracellular membrane. Through the tropomyosin-related kinase B
(TrkB) receptor BDNF can enter the cytoplasmic regulation downstream signaling
pathway. In cytoplasm, A2 and F3 regulate HDAC8 phosphorylation and distribution
to alter HDAC8 activity, which in turn affects the TrkB receptor downstream signaling
pathway, including up-regulating PI3K and MAPK-ERK signaling pathways and
downstream AKT and CREB proteins to promote neural plasticity and learning memory.
In summary, A2 and F3 can influence neuronal plasticity and learning memory
expression by regulating the secretion of BDNF, affecting the TrkB receptor
downstream signaling pathway PI3K, MAPK-ERK and regulating the degree of
HDAC8 phosphorylation and distribution to alter HDAC8 activity.
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