TRANSCRIPTIONAL REGULATION OF HUMAN TRYPTOPHAN HYDROXYLASE 2 GENE PROMOTER

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。色氨酸羟化酶（TPH; EC 1.14.16.6）是5-羟色胺生物合成中的限速酶。在脑、松果体和外周组织中催化L-色氨酸转化为5-羟色氨酸（5-HT）。在大脑中，肾上腺素能神经元几乎只存在于中缝系统中，该系统支配大多数其他大脑区域。多巴胺能神经传递功能障碍与精神分裂症、抑郁症和焦虑症的发病机制有关。经典和现代抗抑郁药物似乎调节5-HT神经传递。鉴于5-羟色胺的重要性和最近发现的TPH 2在大脑中发现的亚型，调查TPH 2的转录调控机制和单核苷酸多态性（SNPs）在这种调节中发挥的作用是必要的。Zhang et al.（2005）和Lemonde et al.（2003）已经表明，TPH 2中存在的SNP和5-HT 1A受体的异常转录调节可能代表单相抑郁症的重要风险因素。TPH相关基因的变异正成为药物治疗反应的重要预测因子，由于TPH能神经传递似乎在情感障碍中起重要作用，我们打算（1）功能性定位野生型TPH 2的启动子区域，（2）研究转录和转录后调控，（3）通过基因分型检测SNP的影响（rs-4570625：G-T;和rs-11178997：T-A）。表征TPH 2启动子和识别转录机制和SNPs发挥的作用，可能有助于阐明治疗精神疾病的新靶点。

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.