Deiodinases in Thyroid Hormone Homeostasis
甲状腺激素稳态中的脱碘酶
基本信息
- 批准号:6822030
- 负责人:
- 金额:$ 13.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-09-01 至 2007-08-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant):
The types 1 and 2 iodothyroinine deiodinases (D1 and D2) are the enzymes which convert the prohormone T4 to the active hormone, T3. The Dio1 gene of humans and mice is highly stimulated by T3, inappropriately enhancing the severity of thyrotoxicosis of the hyperthyroid patient. D1 activity is also used as an index of peripheral thyroid status in transgenic animal models, but nothing is known as to why it is so T3 responsive. There are several genetic models in which the activities of D1 or D2 are reduced or absent. The C3H mouse adapts to a genetic decrease in D1 by increasing T4 to maintain a normal T3 and TSH. The D2 "knockout" mouse (D2KO) also has an elevated serum T4, and a normal T3, but an increased TSH. Surprisingly, these mice also have increased D1 suggesting peripheral compensation has occurred. Similar changes occur in chimeric mice produced by crossing the D2KO and C3H strains. Thus, despite seemingly normal T3 levels, at least one peripheral marker of thyroid status, D1 activity, suggests hyperthyroidism in the latter two mouse models. We hypothesize that increased D1 expression is one of the adaptive mechanisms allowing these animals to compensate for their resistance to T4, but it is not clear how this develops. In Aim I we will define the peripheral thyroid status of mice with impaired T4 activation and determine whether D1 is a reliable peripheral thyroid status marker. Physiological (02 consumption, bone density, growth) and biological ( the levels of T3 responsive mRNAs in various tissues) parameters will define the thyroid status. T4 infusion studies will reveal how the adaptation to the impaired T4 to T3 conversion occurs. The second Aim is to determine the molecular mechanism of the exquisite sensitivity of the Diol gene to T3. Various molecular techniques will elucidate the role of the thyroid response element we have identified in the Diol gene, and determine how it confers such a high T3 response. These studies will define factors increasing T4 to T3 conversion and elucidate how T3 continues to stimulate gene expression even in the hyperthyroid state. Employing these physiological approaches to assess the thyroid status of these mice will aid the candidate in pursing her short-term goal of gaining a solid background working with in vivo models to complement her molecular biological skills. This experience will help her achieve her long-term goal of becoming an independent biomedical scientist.
描述(由申请人提供):
1型和2型碘甲状腺素脱碘酶(D1和D2)是将激素原T4转化为活性激素T3的酶。人和小鼠的Dio1基因被T3高度刺激,不适当地增强甲状腺功能亢进患者的甲状腺毒症的严重程度。在转基因动物模型中,D1活性也被用作外周甲状腺状态的指标,但尚不清楚为什么它对T3如此敏感。有几种遗传模型,其中D1或D2的活性降低或缺失。C3H小鼠通过增加T4来适应D1的遗传减少,以维持正常的T3和TSH。D2“敲除”小鼠(D2KO)也具有升高的血清T4和正常的T3,但是升高的TSH。令人惊讶的是,这些小鼠也具有增加的D1,表明发生了外周代偿。类似的变化发生在通过杂交D2KO和C3H品系产生的嵌合小鼠中。因此,尽管T3水平看似正常,但至少有一种甲状腺状态的外周标志物D1活性表明后两种小鼠模型存在甲状腺功能亢进。我们假设D1表达增加是这些动物补偿其对T4抗性的适应机制之一,但尚不清楚这是如何发展的。在目的I中,我们将定义T4活化受损小鼠的外周甲状腺状态,并确定D1是否是可靠的外周甲状腺状态标志物。生理学(O2消耗、骨密度、生长)和生物学(各种组织中T3响应mRNA的水平)参数将定义甲状腺状态。T4输注研究将揭示如何适应受损的T4到T3转换发生。第二个目的是确定Diol基因对T3的高度敏感性的分子机制。各种分子技术将阐明我们在二醇基因中鉴定的甲状腺反应元件的作用,并确定它如何赋予如此高的T3反应。这些研究将确定增加T4转化为T3的因素,并阐明T3如何在甲状腺功能亢进状态下继续刺激基因表达。采用这些生理学方法来评估这些小鼠的甲状腺状态将有助于候选人追求她的短期目标,即获得与体内模型一起工作的坚实背景,以补充她的分子生物学技能。这段经历将帮助她实现成为一名独立生物医学科学家的长期目标。
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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ANN M ZAVACKI其他文献
ANN M ZAVACKI的其他文献
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{{ truncateString('ANN M ZAVACKI', 18)}}的其他基金
Role of Deiodinases in Thyroid Hormone Homeostasis
脱碘酶在甲状腺激素稳态中的作用
- 批准号:
7256311 - 财政年份:2006
- 资助金额:
$ 13.39万 - 项目类别:
Role of Deiodinases in Thyroid Hormone Homeostasis
脱碘酶在甲状腺激素稳态中的作用
- 批准号:
7777468 - 财政年份:2006
- 资助金额:
$ 13.39万 - 项目类别:
Role of Deiodinases in Thyroid Hormone Homeostasis
脱碘酶在甲状腺激素稳态中的作用
- 批准号:
7135409 - 财政年份:2006
- 资助金额:
$ 13.39万 - 项目类别:
Role of Deiodinases in Thyroid Hormone Homeostasis
脱碘酶在甲状腺激素稳态中的作用
- 批准号:
7625059 - 财政年份:2006
- 资助金额:
$ 13.39万 - 项目类别:
Role of Deiodinases in Thyroid Hormone Homeostasis
脱碘酶在甲状腺激素稳态中的作用
- 批准号:
7853605 - 财政年份:2006
- 资助金额:
$ 13.39万 - 项目类别:
RETINOID SIGNALING BY THE ORPHAN RECEPTOR RIP 14
孤儿受体 RIP 14 的视黄醇信号传导
- 批准号:
2874272 - 财政年份:2000
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$ 13.39万 - 项目类别:
RETINOID SIGNALING BY THE ORPHAN RECEPTOR RIP 14
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6134250 - 财政年份:1999
- 资助金额:
$ 13.39万 - 项目类别:
RETINOID SIGNALING BY THE ORPHAN RECEPTOR RIP 14
孤儿受体 RIP 14 的视黄醇信号传导
- 批准号:
2905161 - 财政年份:1999
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