TRANSCRIPTIONAL REGULATION OF HUMAN TRYPTOPHAN HYDROXYLASE 2 GENE PROMOTER

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。色氨酸羟化酶(TPH；EC 1.14.16.6)是5-羟色胺生物合成的限速酶。它催化L-色氨酸在大脑、松果体和周围组织中转化为5-羟色氨酸(5-HT)。在大脑中，5-羟色胺能神经元几乎只存在于中缝系统，该系统支配着大脑的大多数其他区域。5-羟色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。古典和现代的抗抑郁药物似乎都能调节5-羟色胺的神经传递。鉴于5-羟色胺的重要性和最近在大脑中发现的TPH2的异构体，研究TPH2的转录调控机制以及单核苷酸多态(SNPs)在这种调控中的作用是必要的。张某等人。(2005)和LeMonde等人。(2003)的研究表明，TPH2中存在的SNPs和5-HT1a受体转录调控的异常可能是单相抑郁的重要危险因素。5-羟色胺相关基因的变异正在成为药物治疗反应的重要预测因子，由于5-羟色胺能神经传递似乎在情感性障碍中发挥重要作用，我们打算(1)从功能上定位野生型TPH2的启动子区域，(2)研究转录和转录后调控，(3)通过基因分型在抑郁症和对照组受试者队列中检查SNPs(Rs-4570625：G-T；和Rs-11178997：T-A)的影响。确定TPH2启动子的特征并确定转录机制和SNPs所起的作用，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.