HUMAN TYROSINE HYDROXYLASE AND SCHIZOPHRENIA
人酪氨酸羟化酶与精神分裂症
基本信息
- 批准号:3070326
- 负责人:
- 金额:$ 8.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1992
- 资助国家:美国
- 起止时间:1992-03-01 至 1997-02-28
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
This application for an ADAMHA RSDA (Level II) for Dr. John W. Haycock
focuses on the role of brain catecholamine systems in mental health.
Dopaminergic systems have been implicated in schizophrenia, and the
initial and rate-limiting enzyme in dopamine biosynthesis, tyrosine
hydroxylase (TH), will be studied. Transcriptional, translational and
posttranslational regulation of TH has been demonstrated in a number of
species. Unlike in lower species, however, the messenger RNA encoding
TH (mRNA-TH) in humans (and at least one other primate) undergoes
alternative splicing, resulting in four different species of human mRNA-
TH. In recent work from the applicant's laboratory, protein products
corresponding to all four of these mRNA species have been demonstrated
in human adrenal medulla whereas in the human and monkey nigrostriatal
system, two of the forms predominate. Thus, in humans and primates,
alterations in the different isoforms of TH protein may also be involved
in the regulation of TH activity.
The research proposed in this application involves analysis of the
multiple forms of human TH. (A.) Regional, cellular and subcellular
distributions of the different forms will be studied with immunoblotting
and immunocytochemistry using type-specific antibodies. The regional
distribution of the different forms of mRNA-TH and TH protein will be
determined in brain samples from schizophrenics and various control
groups. (B.) Functional differences between the two major forms will be
evaluated by studying the regulation of site-specific TH phosphorylation
and TH catalytic activity. Ser31 was identified by Dr. Haycock as a
regulated phosphorylation site in TH. In "normally spliced" TH, the
phosphorylation of Ser31 has recently been demonstrated by the applicant
to be directly mediated by MAP2 kinase whereas in the other form abundant
in brain, this serine is within a consensus sequence for phosphorylation
by calcium/calmodulin-dependent protein kinase II. Regulation of TH will
be studied in situ in human neuroblastoma cell lines and in stably
transfected cell lines which express the different forms and in vitro
with purified protein kinases and TH purified from the different cell
lines.
The research development that would be provided by this award includes
the progression of Dr. Haycock's extensive fundamental research
background into the human/clinical arena. The studies will also provide
for the expansion of his areas of expertise into immunocytochemistry and
molecular biology. In terms of professional growth, the award will
facilitate the concerted efforts necessary to bring his multidisciplinary
studies to fruition by preventing further encroachment of departmental
and institutional responsibilities into Dr. Haycock's research time. The
award would also enhance Dr. Haycock's professional status in terms of
consideration for promotion from Associate to Full Professor.
John W. Haycock 博士的 ADAMHA RSDA(二级)申请
重点关注大脑儿茶酚胺系统在心理健康中的作用。
多巴胺能系统与精神分裂症有关,
多巴胺生物合成的起始酶和限速酶,酪氨酸
将研究羟化酶(TH)。 转录、翻译和
TH 的翻译后调控已在许多研究中得到证实
物种。 然而,与低等物种不同的是,编码信使RNA
人类(和至少一种其他灵长类动物)的 TH (mRNA-TH) 经历
选择性剪接,产生四种不同物种的人类 mRNA-
TH。 在申请人实验室的最近工作中,蛋白质产品
已证实对应于所有这四种 mRNA 种类
在人类肾上腺髓质中,而在人类和猴子黑质纹状体中
系统中,有两种形式占主导地位。 因此,在人类和灵长类动物中,
TH 蛋白不同亚型的改变也可能参与其中
TH 活性的调节。
本申请中提出的研究涉及分析
多种形式的人类 TH。 (A.) 区域、细胞和亚细胞
将通过免疫印迹研究不同形式的分布
和使用类型特异性抗体的免疫细胞化学。 区域性
不同形式的 mRNA-TH 和 TH 蛋白的分布将是
在精神分裂症患者和各种对照的大脑样本中确定
组。 (B.) 两种主要形式之间的功能差异将是
通过研究位点特异性 TH 磷酸化的调节进行评估
和TH催化活性。 Haycock 博士将 Ser31 鉴定为
TH 中受调节的磷酸化位点。在“正常拼接”TH 中,
申请人最近已证明 Ser31 的磷酸化
由 MAP2 激酶直接介导,而其他形式则丰富
在大脑中,该丝氨酸位于磷酸化的共有序列内
通过钙/钙调蛋白依赖性蛋白激酶 II。 TH 的监管将
在人神经母细胞瘤细胞系中进行原位研究并稳定地
表达不同形式和体外的转染细胞系
含有纯化的蛋白激酶和从不同细胞纯化的 TH
线。
该奖项将提供的研究进展包括
海考克博士广泛的基础研究的进展
人类/临床领域的背景。研究还将提供
将他的专业领域扩展到免疫细胞化学和
分子生物学。 在专业成长方面,该奖项将
促进必要的协同努力,使他的多学科
通过防止进一步侵犯部门职能,使研究取得成果
海考克博士的研究时间和机构责任。 这
该奖项还将提升海考克博士在以下方面的专业地位:
考虑从副教授晋升为正教授。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JOHN W HAYCOCK其他文献
JOHN W HAYCOCK的其他文献
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