TRANSCRIPTIONAL REGULATION OF HUMAN TRYPTOPHAN HYDROXYLASE 2 GENE PROMOTER

这个子项目是众多研究子项目之一

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tryptophan hydroxylase (TPH; EC 1.14.16.6) is the rate-limiting enzyme in the biosynthesis of serotonin. It catalyzes the conversion of L-tryptophan into 5-hydroxytryptophan (5-HT) in the brain, pineal gland, and peripheral tissues. In the brain serotonergic neurons are almost exclusively present in the raphe system, which innervates most of the other brain regions. Dysfunction of serotonergic neurotransmission has been implicated in the pathogenesis of schizophrenia, depression, and anxiety. Classical as well as modern antidepressant drugs appear to modulate 5-HT neurotransmission. Given the importance of serotonin and the recent discovery of TPH2 as an isoform found in the brain, investigating the transcriptional regulatory mechanisms of TPH2 and the role single nucleotide polymorphisms (SNPs) play in this regulation is a necessity. Zhang et al. (2005) and Lemonde et al. (2003) have shown that SNPs present in TPH2 and abnormal transcriptional regulation of the 5-HT1A receptor may represent important risk factors for unipolar depression. Variations in serotonin-related genes are becoming important predictors of response to drug treatment and since serotonergic neurotransmission appears to play an important role in affective disorders we intend to (1) functionally map the promoter region of wild type TPH2, (2) study transcriptional and post-transcriptional regulation and (3) examine through genotyping the influence of SNPs (rs-4570625:G-T; and rs-11178997: T-A) in cohorts of depressed and control subjects. Characterizing the TPH2 promoter and identifying transcriptional mechanisms and the role SNPs play, may help to elucidate novel targets for treatment of mental illness.