CN109364251A - Tet蛋白在治疗抑郁症中的应用 - Google Patents

Tet蛋白在治疗抑郁症中的应用 Download PDF

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CN109364251A
CN109364251A CN201811487487.5A CN201811487487A CN109364251A CN 109364251 A CN109364251 A CN 109364251A CN 201811487487 A CN201811487487 A CN 201811487487A CN 109364251 A CN109364251 A CN 109364251A
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albumen
depression
tet1
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徐兴顺
金鹏
孙淼
苗志刚
程郢
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Suzhou University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/24—Antidepressants

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Abstract

本发明涉及生物技术领域，尤其是TET蛋白在治疗抑郁症中的应用。该发明为：TET1蛋白在治疗抑郁症药物中的应用。本发明通过在小鼠实验中获得的数据显示，TET1蛋白的抑制乃至敲除都并未给小鼠带来其他任何异状。因此本申请中TET1蛋白作为靶向药的靶点，可以避免原治疗抑郁症药物的副作用。

Description

TET蛋白在治疗抑郁症中的应用
技术领域
本发明涉及生物技术领域，尤其是TET蛋白在治疗抑郁症中的应用。
背景技术
抑郁症是躁狂抑郁症的一种发作形式，以情感低落、思维迟缓、以及言语动作减少，迟缓为典型症状。抑郁症严重困扰患者的生活和工作，给家庭和社会带来沉重的负担，约15％的抑郁症患者死于自杀。世界卫生组织、世界银行和哈佛大学的一项联合研究表明，抑郁症已经成为中国疾病负担的第二大病。
目前抑郁症患者有效治愈率不足2/3，而且明显的药物副作用困扰着大多数抑郁症患者。因此抑郁症的研究成为热点和难点，对发病机制的进一步研究和新型药物的开发是解决这一社会健康问题的重中之重。原有治疗抑郁的药物都基于影响神经递质5-HT的再摄取而开发来的，这一类药物对抑郁症的治疗有一定的效果，但是副作用都较大。
发明内容
本发明要解决的技术问题是：为了解决背景技术中描述的技术问题，本发明提供了一种TET蛋白在治疗抑郁症中的应用，通过在小鼠实验中获得的数据显示，TET1蛋白的抑制乃至敲除都并未给小鼠带来其他任何异状。因此本申请中TET1蛋白作为靶向药的靶点，可以避免原治疗抑郁症药物的副作用。
一种TET蛋白在治疗抑郁症中的应用，TET1蛋白在治疗抑郁症药物中的应用。
具体地，所述TET1蛋白作为治疗抑郁症药物的一个靶点。
具体地，所述TET1蛋白的序列为：
本发明的有益效果是：本发明提供了一种TET蛋白在治疗抑郁症中的应用，通过在小鼠实验中获得的数据显示，TET1蛋白的抑制乃至敲除都并未给小鼠带来其他任何异状。因此本申请中TET1蛋白作为靶向药的靶点，可以避免原治疗抑郁症药物的副作用。
附图说明
下面结合附图和实施例对本发明进一步说明。
图1是本发明的悬尾实验数据图；
图2是本发明的强迫游泳实验数据图；
图3是本发明的检测TET1基因mRNA水平的QPCR结果数据图；
图4是本发明的检测TET2基因mRNA水平的QPCR结果数据图；
图5是本发明的检测TET3基因mRNA水平的QPCR结果数据图；
图6本发明的免疫共沉淀实验对照图；
图7本发明的可视化测序分析图；
具体实施方式
现在结合附图对本发明作进一步详细的说明。
图1是本发明的悬尾实验数据图，图2是本发明的强迫游泳实验数据图，图3是本发明的检测TET1基因mRNA水平的QPCR结果数据图，图4是本发明的检测TET2基因mRNA水平的QPCR结果数据图，图5是本发明的检测TET3基因 mRNA水平的QPCR结果数据图，图6本发明的免疫共沉淀实验对照图，图7本发明的可视化测序分析图。
一种TET蛋白在治疗抑郁症中的应用，TET1蛋白在治疗抑郁症药物中的应用。所述TET1蛋白作为治疗抑郁症药物的一个靶点。所述TET1蛋白的序列为：
在对长期处于不同刺激压力下的模型小鼠的研究过程中发现小鼠表现出抑郁样行为，同时PFC(Prefrontal cortex)中的5羟甲基化胞嘧啶(5hmC)明显下降。因而对介导5hmC变化的TET家族进行进一步实验。mRNA检测结果显示 CRS小鼠PFC中TET1明显下降，而TET2和TET3则无显著变化。为了进一步探究TET家族在其中还作用的机制，从而构建了TET1敲除(Knock out)和TET2 选择性敲除的小鼠，小鼠的行为学检测结果显示TET1KO小鼠具有更加的活泼、好动的表现，而TET2CKO的小鼠不动时间明显的增长，这些行为学结果跟此前的研究结果一致。这些结果都显示Tet1基因可以作为治疗抑郁的一个靶点。
结合附图1和附图2所示，悬尾实验和强迫游泳实验是检测小鼠是否有抑郁样行为的通用方法，从图中可以看出Tet1基因敲除小鼠具有明显的抗抑郁作用，不动时间明显减少(不动时间越长表明小鼠抑郁越严重)。
表1为悬尾实验的数据表格：
表2为强迫游泳实验的数据表格：
结合附图3、附图4和附图5所示，QPCR结果是用来检测基因的转录水平，也可代表基因的蛋白水平。从附图3、附图4和附图5中可以看出在给与小鼠应激之后小鼠脑组织中的TET1基因转录明显减少，而TET2和TET3则没有改变。 (对照组是正常小鼠，应激组指抑郁造模组即有抑郁样行为的小鼠)
表3为附图3、附图4和附图5的对应数据表格：
使用一种选择性的化学标签对慢性应激小鼠进行了DNA 5hmC高通量测序，发现低氧诱导因子(Hypoxia-induced factor,HIF)在5hmC的动态变化中有重要作用。
表4为DNA 5hmC高通量测序分析结果表：
这是因为外界应激造成的相关DNA 5hmC变化位点都存在着HIF的结合结构域(HIFbinding regions,HBR)。
如附图6所示，虽然应激后脑内HIF1α蛋白水平没有变化，但是HIF1α和 Tet1的相互作用明显增强。如附图7所示，进一步CHIP-seq等实验证实存在 HBR的相关基因能够与HIF1α结合，影响了其DNA 5hmC的改变和蛋白的表达，而这些基因的表达改变与抑郁症密切相关已经被证实。以上这些结果可以证明，Tet1蛋白可以通过HIF1a蛋白来影响抑郁相关基因的表达，从而起到调控抑郁行为发生的作用。从更深层次说明，Tet1蛋白可以作为研发抗抑郁药的一个有效靶点。
以上述依据本发明的理想实施例为启示，通过上述的说明内容，相关工作人员完全可以在不偏离本项发明技术思想的范围内，进行多样的变更以及修改。本项发明的技术性范围并不局限于说明书上的内容，必须要根据权利要求范围来确定其技术性范围。

Claims (3)

1.一种TET蛋白在治疗抑郁症中的应用，其特征在于，TET1蛋白在治疗抑郁症药物中的应用。
2.根据权利要求1所述的TET蛋白在治疗抑郁症中的应用，其特征在于：所述TET1蛋白作为治疗抑郁症药物的一个靶点。
3.根据权利要求1所述的TET蛋白在治疗抑郁症中的应用，其特征在于：所述TET1蛋白的序列为：
CN201811487487.5A 2018-12-06 2018-12-06 Tet蛋白在治疗抑郁症中的应用 Pending CN109364251A (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114195902A (zh) * 2021-10-18 2022-03-18 翌圣生物科技(上海)股份有限公司 重组蛋白结构域增强tet酶及全基因组dna甲基化检测方法

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WO2014047447A2 (en) * 2012-09-21 2014-03-27 Midwestern University Fto modulating compounds and methods of use

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2014047447A2 (en) * 2012-09-21 2014-03-27 Midwestern University Fto modulating compounds and methods of use

Non-Patent Citations (4)

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Title
ANDRII RUDENKO ET AL.: "Tet1 is critical for neuronal activity-regulated gene expression and memory extinction", 《NEURON》 *
JIAN FENG ET AL.: "Tet1 in Nucleus Accumbens Opposes Depression- and Anxiety-Like Behaviors", 《NEUROPSYCHOPHARMACOLOGY》 *
YA BIN WEI ET AL.: "Antidepressant-Like Effect of Sodium Butyrate is Associated with an Increase in TET1 and in 5-Hydroxymethylation Levels in the Bdnf Gene", 《INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY》 *
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114195902A (zh) * 2021-10-18 2022-03-18 翌圣生物科技(上海)股份有限公司 重组蛋白结构域增强tet酶及全基因组dna甲基化检测方法
CN114195902B (zh) * 2021-10-18 2023-06-20 翌圣生物科技(上海)股份有限公司 重组蛋白结构域增强tet酶及全基因组dna甲基化检测方法

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Application publication date: 20190222