WO2021147977A1 - Synaptotagmin-7在双向情感障碍诊断和治疗中的用途 - Google Patents

Synaptotagmin-7在双向情感障碍诊断和治疗中的用途 Download PDF

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WO2021147977A1
WO2021147977A1 PCT/CN2021/073202 CN2021073202W WO2021147977A1 WO 2021147977 A1 WO2021147977 A1 WO 2021147977A1 CN 2021073202 W CN2021073202 W CN 2021073202W WO 2021147977 A1 WO2021147977 A1 WO 2021147977A1
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syt7
bipolar disorder
gene
expression product
mice
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PCT/CN2021/073202
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English (en)
French (fr)
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姚骏
沈伟
王秋文
刘要南
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清华大学
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Priority to JP2022537020A priority Critical patent/JP2023506637A/ja
Priority to US17/794,541 priority patent/US20230003717A1/en
Priority to CA3164847A priority patent/CA3164847A1/en
Priority to AU2021210069A priority patent/AU2021210069A1/en
Priority to KR1020227025304A priority patent/KR20220130704A/ko
Priority to EP21743632.8A priority patent/EP4067504A4/en
Publication of WO2021147977A1 publication Critical patent/WO2021147977A1/zh

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Definitions

  • the invention relates to the field of biomedicine, in particular to the use of Synaptotagmin-7 in the diagnosis and treatment of bipolar disorder.
  • Single-cell sequencing technology is one of the most popular technologies in the past decade, and it has shown a very broad application prospect in development, tumor-related scientific research and disease diagnosis.
  • single-cell sequencing technology has been realized at different levels of genome, transcriptome, epitome, and proteome, and it has played an important role in the research of many scientific issues.
  • the current single-cell sequencing technology has many challenges in terms of data quality, throughput, cost, operability, etc., and there are still many technical barriers to true large-scale application.
  • BD Bipolar disorder
  • WHO World Health Organization
  • neuropsychiatric diseases including BD
  • BD neuropsychiatric diseases
  • the genetic defects of multiple genes need to work together to show the clinical symptoms of the disease.
  • Finding and repairing these defects is to understand the pathogenic mechanism of BD and explore the clinical practice of BD.
  • the key to treatment. Therefore, identifying the defects of key molecular signaling pathways in BD patients is the most important task for biologists and medical experts studying BD.
  • an object of the present invention is to propose a use of Synaptotagmin-7 (abbreviated as Syt7) in the diagnosis and treatment of bipolar disorder.
  • the present invention provides the following technical solutions:
  • the present invention provides a biomarker for bipolar disorder, the biomarker including Syt7 gene and/or its expression product.
  • the present invention provides a use of Syt7 gene and/or its expression product in the preparation of a medicine for the treatment of bipolar disorder and/or its complications.
  • the expression product of Syt7 gene can be used as a protein drug.
  • the drug can increase the expression of Syt7 gene.
  • the present invention provides a bipolar disorder cell model. Compared with wild-type cells, the amount of Syt7 gene and/or its expression product contained in the bipolar disorder cell model is reduced.
  • the present invention provides an animal model of bipolar disorder. Compared with wild-type animals, the amount of Syt7 gene or its expression product contained in the animal model of bipolar disorder is reduced. The expression of Syt7 gene in the provided bipolar disorder model animal is suppressed.
  • the provided bipolar disorder model animal may be a mouse, which can inactivate Syt7 by replacing the C2A domain of the Syt7 gene with a neomycin gene fragment.
  • Those skilled in the art can know that when obtaining the bidirectional emotional model animal, it is also possible to obtain inactivated Syt7 by replacing or knocking out other active regions on the Syt7 gene. Commonly used methods can be achieved by gene recombination or CRISPR methods commonly used in the art.
  • the model animals can be mice, rats, or non-human primates, such as monkeys.
  • the animal includes at least one selected from the group consisting of mice, rats, or primates.
  • the present invention provides a method for screening drugs for the treatment of bipolar disorder, comprising: administering the candidate drug to the bipolar disorder cell model described in the third aspect of the present invention or the second aspect of the present invention.
  • the animal model of bipolar disorder described in the four aspects screening candidate drugs that increase the amount of Syt7 gene or its expression product, or screening candidate drugs that reduce the symptoms of bipolar disorder, as the drug for the treatment of bipolar disorder .
  • the bipolar disorder model animal may be a mouse whose Syt7 gene expression is inhibited or protein activity is inhibited.
  • the candidate drug can also be administered to non-human mammalian cells, and if the Syt7 gene expression level or protein activity in the non-human mammal or cell is up-regulated, the candidate drug is determined to be effective.
  • the present invention provides a kit including reagents for specifically detecting the Syt7 gene and/or its expression product.
  • a kit containing a reagent for specifically detecting the Syt7 gene and/or its expression product can be used for real-time detection and monitoring of bipolar disorder.
  • the reagent includes primers and/or probes. The application of specific probes or primers can be used to detect the expression level of Syt7 or its expression products.
  • primers and probes it can also be equipped with other commonly used reagents for gene or protein expression, such as buffer for polymerase chain reaction, SDS-PAGE detection solution for protein expression detection, etc. Wait.
  • the present invention provides a system for diagnosing bipolar disorder or judging the prognostic effect of bipolar disorder, comprising: an obtaining device for obtaining the Syt7 gene or its expression product in a biological sample A judgment device, the judgment device is connected to the obtaining device, and the judgment device is used for diagnosing bipolar disorder or judging the prognostic effect of bipolar disorder based on the amount of Syt7 gene or its expression product in the biological sample.
  • the judging device further includes: the amount of Syt7 gene or its expression product in the biological sample is lower than the amount of Syt7 gene or its expression product in a normal sample, and the biological sample suffers from two-way emotion.
  • An indication of a disorder; or the amount of Syt7 gene or its expression product in the biological sample is at least not less than the amount of Syt7 gene or its expression product in a normal sample, which is an indicator that the bipolar disorder patient has a good prognostic effect.
  • the present invention provides a method for diagnosing whether a subject suffers from bipolar disorder, which includes detecting the Syt7 gene and/or its expression product in a biological sample from the subject.
  • the present invention provides a method for diagnosing whether a subject suffers from bipolar disorder, including detecting the expression level of Syt7 gene in a biological sample from the subject. If the expression level of Syt7 gene in the subject is significantly lower than the normal level, then Based on this, it can be determined that the subject suffers from bipolar disorder.
  • Figure 1 is a diagram of the results of identifying Syt7 as a candidate risk factor involved in abnormal behaviors according to an embodiment of the present invention.
  • a and B in Figure 1 show the expression of 18 candidate genes in hippocampal neurons differentiated from induced pluripotent stem cells (iPSC), and A in Figure 1 shows the results of transcriptome sequencing (RNA-seq),
  • Figure 1 Panel B shows the results of real-time fluorescent quantitative RT-PCR.
  • C in Figure 1 shows the resting time of the mice in the forced swimming behavior test (FST).
  • FST forced swimming behavior test
  • Fig. 2 is a graph showing the results of under-expression of Syt7 in hippocampal neurons differentiated from induced pluripotent stem cells (iPSC) of BD patients according to an embodiment of the present invention.
  • a and B in Figure 2 show the expression of Syt7 in a type of hippocampal neurons derived from LR and NR patients.
  • a in Figure 2 shows the results of real-time fluorescent quantitative RT-PCR, and B in Figure 2 shows the western blot.
  • HC represents the healthy control group
  • n 4 people
  • LR represents the lithium salt response group
  • n 3 people
  • NR represents the lithium salt non-reactive group
  • Figure 3 shows the immobile time of wild-type mice and Syt7 KO mice in the night and day forced swimming experiments (FST) provided by an embodiment of the present invention.
  • Figure 3 shows the resting time of Syt7KO mice showing circadian rhythm fluctuations and the shortening of the continuous resting time of Syt7KO mice.
  • FIG 4 is a diagram showing the results of Syt7KO mice having behavioral defects according to an embodiment of the present invention.
  • SPT sugar preference test
  • E is the result of the schizophrenia test of Syt7 KO mice.
  • FIG. 5 shows the therapeutic effect of psychotropic drugs olanzapine and lithium salt on abnormal behavior in Syt7 KO mice according to an embodiment of the present invention.
  • a and B in Figure 5 are in the night (A) and day (B) forced swimming experiment (FST), intraperitoneal injection of olanzapine (OLZ) (0.2-1.0 mg/kg) on the resting time of mice Impact.
  • FIG. 6 The therapeutic effect of high-dose olanzapine (1.0 mg/kg) injection provided according to an embodiment of the present invention on abnormal behavior of Syt7 KO mice.
  • a in Figure 6 represents the results of the impact on the number of failed escapes in the LH test
  • B represents the results of the impact on the preference of sugar water in the SPT test
  • C represents the results of the impact on the residence time of the light in the LDB test.
  • Fig. 7 shows the therapeutic effect of intraperitoneal injection of lithium salt (30 mg/kg) on abnormal behavior of Syt7 KO mice according to an embodiment of the present invention.
  • A shows the influence on the resting time of mice in the FST experiment
  • B shows the influence on the number of failed escapes in the LH test
  • C shows the influence on the sugar preference in the SPT test
  • D shows the influence on the LDB The impact of the residence time in the bright spot in the test.
  • n 8 using Student's t-test; *P ⁇ 0.05; error bars, sem.
  • Fig. 8 is the detection result of the level of Syt7 mRNA in the plasma of BD patients according to an embodiment of the present invention, showing the results of quantitative analysis of Syt7 mRNA in 20 BD patients and 11 healthy controls.
  • Fig. 9 is a graph showing the detection results of Syt7 mRNA levels in plasma of BD patients with different BD disease types, BD family history, drug treatment, and whether there is mental disorder according to an embodiment of the present invention.
  • Fig. 10 is a schematic diagram of a system for diagnosing bipolar disorder or judging the prognosis effect of bipolar disorder according to an embodiment of the present invention.
  • the present invention provides a biomarker for bipolar disorder, the biomarker including Syt7 gene and/or its expression product.
  • biomarker has a general meaning in the art, which can mean a biomolecule and/or its detectable part, and qualitatively or quantitatively evaluate it to obtain predictive information or diagnostic information.
  • the state of the subject with respect to a given disease or condition can be characterized by detecting corresponding biomarkers in the subject.
  • Biomarkers can be genes, proteins or peptides and so on.
  • the present invention also provides a use of the Syt7 gene and/or its expression product in the preparation of a medicine for the treatment of bipolar disorder and/or its complications.
  • the expression product of Syt7 gene can be used as a protein drug.
  • the content of the expression product of Syt7 gene in the body can be increased, so that it can be used to treat bipolar disorder. Or complications.
  • the present invention also provides a method for diagnosing whether a subject suffers from bipolar disorder, which includes detecting the Syt7 gene and/or its expression product in a biological sample from the subject.
  • a subject or patient when a subject or patient is mentioned, it usually refers to a human being, of course, it can also include non-human animals as needed, preferably warm-blooded animals, more preferably viviparous animals, and more preferably mammals.
  • the present invention also provides a system for diagnosing biaffective disorder or judging the prognostic effect of biaffective disorder, as shown in FIG. 10, comprising: an obtaining device for obtaining a biological sample The amount of Syt7 gene or its expression product; a judgment device, the judgment device is connected to the obtaining device, and the judgment device is used for diagnosing bipolar disorder or judgment based on the amount of Syt7 gene or its expression product in the biological sample The prognostic effect of bipolar disorder.
  • the judging device further includes: the amount of Syt7 gene or its expression product in the biological sample is lower than the amount of Syt7 gene or its expression product in a normal sample, and the biological sample suffers from two-way emotion.
  • An indication of a disorder; or the amount of Syt7 gene or its expression product in the biological sample is at least not less than the amount of Syt7 gene or its expression product in a normal sample, which is an indicator that the bipolar disorder patient has a good prognostic effect.
  • the amount of Syt7 gene or its expression product in the biological sample is at least 0.5 times lower than the amount of Syt7 gene or its expression product in a normal sample, preferably 1 time, which is that the biological sample suffers from Instructions for bipolar disorder.
  • sample or “biological sample” may include any biological sample from a subject. Including but not limited to whole blood, plasma, serum, red blood cells, white blood cells (e.g., peripheral blood mononuclear cells), saliva, urine, stool (ie stool), tears, sweat, sebum, nipple aspirates, catheter lavage, Tumor exudate, synovial fluid, cerebrospinal fluid, lymphoid fluid, fine needle aspirate, amniotic fluid, any other body fluid, cell lysate, cell secretion products, inflammatory fluid.
  • it may be plasma, serum, or cell pellet.
  • bipolar disorder is also often referred to as bipolar disorder in the art.
  • the bipolar disorder mentioned includes type I bipolar disorder (also known as BD-I type), type II bipolar disorder (also known as BD-II type), and mixed types.
  • the Syt7 gene and its expression product can preferably be used as a biomarker for type I bipolar disorder, to indicate whether or not to suffer from type I bipolar disorder, as well as drug prognostic treatment and so on.
  • type I bipolar disorder is a typical major mania major depression, that is, depression and mania are of the same severity and are both severe.
  • type II bipolar disorder is a typical hypomanic major depression, that is, mania is mild, and the degree is significantly lower than the incidence of depression.
  • the mixed type mainly refers to the simultaneous occurrence of manic symptoms and depressive symptoms in one episode, which is relatively rare in clinical practice.
  • bipolar disorder refers to the disease caused by the development of bipolar disorder.
  • This complication can be accompanied by bipolar disorder, or it can be different from bipolar disorder.
  • Other illnesses For example, it can be type I bipolar disorder comorbid obsessive-compulsive disorder (OCD), which is usually accompanied by social phobia, anxiety (avoidance) personality disorder, and less psychotic symptoms.
  • OCD obsessive-compulsive disorder
  • Example 1 Syt7 is identified as a candidate risk factor for neuropsychiatric disease-similar behavior
  • the GeneCards database was investigated using the keywords insulin (diabetes) and synapses, and it was found that 97 genes were simultaneously present in insulin metabolism and synaptic function.
  • NCBI literature search www.ncbi.nlm.nih.gov/pubmed/
  • 97 genes 18 genes that may play a role in the above two symptoms were screened.
  • RNA-seq and qRT-PCR were used to find 11 of the 18 genes, and the mRNA expression level showed more than 1.5-fold changes (as shown in A and B in Figure 1. It is shown that the change value of the ordinate shown specifically can be expressed as an increase or a decrease).
  • a in Figure 1 is the result of transcriptome sequencing (RNA-seq) of 18 candidate genes in iPSC-differentiated hippocampal neurons of BD patients;
  • B in Figure 1 is the result of 18 candidate genes in iPSC-differentiated hippocampal neurons of BD patients
  • Syt7 KO mice ie, Syt7 knockout mice
  • ZT 12-24 the night phase
  • ZT 0-12 the day phase
  • the continuous manic result can be expressed in English by Manic-like
  • more than 60% of KO mice exhibited a fluctuating behavioral abnormal phenotype, that is, the resting time in the night phase is shorter and the diurnal resting time is longer (as shown in Figure 3, the bipolar fluctuation results, English can be expressed as Fluctuation).
  • LH is related to depression.
  • SPT sugar water preference test
  • mice were monitored for 24 hours using an open field experiment. It was found that Syt7KO mice had increased activity in the night phase, but in the The diurnal activity decreased, which corresponds to the conclusions obtained from the FST experiment and the tail suspension experiment. Importantly, the changes in the activity of Syt7KO mice persisted in the night and day phases, indicating that the emotional abnormalities of the mice were persistent.
  • Syt7KO mice were treated with the atypical antipsychotic drug olanzapine (OLZ), and the dose-dependent relationship was observed (the doses used were 0.2, 0.5 and 1.0 mg/kg, respectively) (using ANOVA statistical method).
  • OTZ atypical antipsychotic drug olanzapine
  • the Syt7KO mice in the drug treatment group were sufficient to change the behavioral abnormalities (that is, the night phase was relatively short under the action of the medium dose of olanzapine).
  • the resting time is reversed); further, the high-dose olanzapine treatment prolongs the resting time of the diurnal phase.
  • results show that the clinical treatment of BD patients has a significant effect on the abnormal behavior of Syt7KO mice.
  • BD patients were grouped according to age, gender and severity of pathological process.
  • the Syt7mRNA levels of most BD patients showed a downward trend; we noticed that the Syt7mRNA levels of patients over 30 years old did not decrease significantly.
  • the sample size is small, the results still suggest that Syt7 defects may be more obvious in young adults.
  • the plasma Syt7mRNA levels of BD-I and BD-II patients were significantly reduced (as shown in A in Figure 9).
  • first and second are only used for descriptive purposes, and cannot be understood as indicating or implying relative importance or implicitly indicating the number of indicated technical features. Therefore, the features defined with “first” and “second” may explicitly or implicitly include at least one of the features. In the description of the present invention, “plurality” means at least two, such as two, three, etc., unless otherwise specifically defined.

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Abstract

提供了一种用于双向情感障碍的生物标志物，包括Syt7基因和/或其表达产物。还提供了Syt7基因和/或其表达产物在制备药物中的用途，所述药物用于治疗双向情感障碍。通过监控Syt7基因和/或其表达产物，可用于筛选用于治疗双向情感障碍的药物，为能够靶向Syt7分子的诊断和治疗提供帮助。

Description

Synaptotagmin-7在双向情感障碍诊断和治疗中的用途
本申请要求申请号为202010075636.8，申请日为2020年01月22日的中国专利申请的优先权，并将其全部内容引用到本申请中。
技术领域
本发明涉及生物医药领域，具体涉及Synaptotagmin-7在双向情感障碍诊断和治疗中的用途。
背景技术
单细胞测序技术是近十年来最热门的技术之一，在发育，肿瘤相关的科学研究以及疾病诊断方面都展示了十分广泛的应用前景。目前单细胞测序技术在基因组、转录组、表观组和蛋白质组等不同水平都已经实现，并且在很多科学问题的研究中已经发挥着重要的作用。然而目前单细胞测序技术在数据质量，通量，成本，可操作性等方面都存在诸多挑战，真正大规模应用还存在许多技术壁垒。
基于微流控系统的双相情感障碍(bipolar disorder，BD)是一种典型的神经精神疾病，病人饱受躁狂和抑郁这两种极端情绪交替发作的折磨。BD在全球范围内发病率超过1％，并且有15％病人因为得不到及时救治而自杀。因此，BD被世界卫生组织(WHO)列为发病率和劳动丧失率最高的疾病之一。临床研究利用全基因组关联分析发现了BD的一系列易感基因，这些基因曾被认为是与BD的遗传和致病机理有关。然而，基于这些易感基因的遗传动物模型并没有能够显示出BD的临床特点，尤其是躁狂和抑郁自发交替循环的核心症状。因此，产生了这样一个假说，即包括BD在内的神经精神疾病是多基因遗传疾病，需要有多个基因的遗传缺陷共同作用才能表现出疾病的临床症状。然而，具有各种不同易感基因的病人之所以能够表现出相似的临床行为症状，是因为他们具有普遍相同的生物学缺陷，找到并修复这些缺陷是理解BD的致病机理和探索BD的临床治疗方法的关键所在。因而，鉴定BD病人中的关键的分子信号通路的缺陷，是研究BD的生物学家和医学专家最重要的任务。
临床研究已经鉴定了一些易感基因，它们可能参与BD的遗传和病理发生过程。例如，CLOCK基因的一个突变体(它的发现来自一群BD病人)，当在小鼠上表达，小鼠行为表现异常，有些类似于人类躁狂(mania)表征。但是，这些基因仅代表一小部分临床病例的 情况；并且，基于这些基因的遗传动物模型并没有展现出自发的躁狂和抑郁情绪周期循环，然后这又对BD病人来说又是一核心症状。
因此，针对双向情感障碍疾病的研究还需要进一步改进。
发明内容
本发明旨在至少在一定程度上解决相关技术中的技术问题之一。为此，本发明的一个目的在于提出一种Synaptotagmin-7(缩写为Syt7)在双向情感障碍诊断和治疗中的用途。
发明人通过研究发现，双向情感障碍病人的诱导多能干细胞(iPSC)分化出的海马神经元中，Syt7基因表达出现了明显的缺陷；Syt7基因缺失小鼠表现出双向情感障碍的躁狂与抑郁自发循环的症状；并且，BD病人血浆中Syt7 mRNA的表达水平，同健康对照组比较，有明显减低；血细胞中Syt7mRNA水平也减低，结果同血浆中的检测一致。Syt7基因相关的信号通路及其表达产物在双向情感障碍的情绪循环中起到关键作用，靶向Syt7基因相关信号通路的分子，能够对诊断和治疗双向情感障碍提供帮助。
具体而言，本发明提供了如下技术方案：
在本发明的第一方面，本发明提供了一种用于双向情感障碍的生物标志物，所述生物标志物包括Syt7基因和/或其表达产物。
在本发明的第二方面，本发明提供了一种Syt7基因和/或其表达产物在制备药物中的用途，所述药物用于治疗双向情感障碍和/或其并发症。根据本发明的实施例，Syt7基因的表达产物可以作为蛋白药物，通过给予双向情感障碍患者或其并发症患者适量的蛋白药物，提高Syt7基因表达产物在体内含量，从而可以用于治疗双向情感障碍或者并发症。
根据本发明的实施例，所述药物能够使得Syt7基因的表达量增多。
在本发明的第三方面，本发明提供了一种双向情感障碍细胞模型，与野生型细胞相比，所述双向情感障碍细胞模型中含有的Syt7基因和/或其表达产物的量降低。
在本发明的第四方面，本发明提供了一种双向情感障碍动物模型，与野生型动物相比，所述双向情感障碍动物模型中含有的Syt7基因或其表达产物的量降低。所提供的双向情感障碍模式动物中Syt7基因的表达被抑制。根据本发明的实施例，所提供双向情感障碍模式动物可以为小鼠，其可以通过将Syt7基因的C2A结构域替换成neomycin基因片段以达到失活Syt7失活的目的。本领域技术人员可知的是，在获得该双向情感模式动物时，也可以通过对Syt7基因上的其他活性区域进行替换或者敲除，来获得失活的Syt7。常用的手段可 以是本领域常用的基因重组或CRISPR方法来实现，所述模式动物可以是小鼠、大鼠，或非人灵长类动物，例如猴子等等。
根据本发明的实施例，所述动物包括选自小鼠、大鼠或者灵长类动物中的至少一种。
在本发明的第五方面，本发明提供了一种筛选用于治疗双向情感障碍的药物的方法，包括：将候选药物施用于本发明第三方面所述的双向情感障碍细胞模型或者本发明第四方方面所述的双向情感障碍动物模型；筛选使得Syt7基因或其表达产物的量上升的候选药物，或者筛选使得双向情感障碍症状减轻的候选药物，作为所述用于治疗双向情感障碍的药物。通过将候选药物施用于双向情感障碍模式动物，并对所述模式动物的行为进行监测，如果双向情感障碍症状减轻或Syt7基因表达上调或蛋白质活性增强，则判定所述候选药物有效。根据本发明的实施例，所述双向情感障碍模式动物可以为Syt7基因表达被抑制或蛋白质活性被抑制的小鼠。也可以将候选药物给予非人哺乳动物细胞，如果所述非人哺乳动物或细胞中的Syt7基因表达水平或蛋白质活性被上调，则判定所述候选药物有效。
在本发明的第六方面，本发明提供了一种试剂盒，包括特异性检测Syt7基因和/或其表达产物的试剂。利用包含特异性检测Syt7基因和/或其表达产物的试剂的试剂盒，可以用于双向情感障碍的实时检测和监控。根据本发明的实施例，所述试剂包括引物和/或探针。应用特异性探针或者引物，能够用于检测Syt7或其表达产物的表达水平。当然，除了引物和探针之外，还可以配有基因或者蛋白表达的常用其他试剂，例如用于聚合酶链式反应的缓冲液，用于蛋白表达量检测的SDS-PAGE检测用的溶液等等。
在本发明的第七方面，本发明提供了一种诊断双向情感障碍或判断双向情感障碍预后效果的系统，包括：获得装置，所述获得装置用于获得生物样品中Syt7基因或其表达产物的量；判断装置，所述判断装置与所述获得装置相连，所述判断装置用于基于所述生物样品中Syt7基因或其表达产物的量，诊断双向情感障碍或判断双向情感障碍预后效果。
根据本发明的实施例，所述判断装置进一步包括：所述生物样品中Syt7基因或其表达产物的量低于正常样本中Syt7基因或其表达产物的量，是所述生物样品患有双向情感障碍的指示；或所述生物样品中Syt7基因或其表达产物的量至少不低于正常样本中Syt7基因或其表达产物的量，是所述双向情感障碍患者预后效果良好的指示。
在本发明的第八方面，本发明提供了一种诊断受试者是否患有双向情感障碍的方法，包括对来自所述受试者的生物样品中Syt7基因和/或其表达产物进行检测。本发明提供了诊断 受试者是否患有双向情感障碍的方法，包括检测来自受试者的生物样本中Syt7基因的表达水平，如果受试者的Syt7基因的表达水平显著低于正常水平，则可以据此判定该受试者患有双向情感障碍。
附图说明
图1为根据本发明的实施例提供的鉴定Syt7作为候选风险因子参与行为异常的结果图。其中图1中A和B显示了18个候选基因在诱导多能干细胞(iPSC)分化的海马神经元中表达情况，其中图1中A显示了转录组测序(RNA-seq)的结果，图1中B显示了实时荧光定量RT-PCR的结果。图1中C显示了强迫游泳行为测试(FST)中小鼠静止的时间。
图2为根据本发明的实施例提供的经证实的在BD病人的诱导多能干细胞(iPSC)分化的海马神经元中Syt7表达不足的结果图。其中图2中A和B显示了Syt7在LR和NR病人来源的一类海马神经元中表达情况，其中图2中A显示了实时荧光定量RT-PCR的结果，图2中B显示了免疫印迹及其定量分析的结果，其中HC代表健康对照组，n＝4人，LR代表锂盐反应组，n＝3人，NR代表锂盐不反应组，n＝3人。图2中C显示了Syt7在LR和NR病人来源的另一类海马神经元中的表达情况，其中HC代表健康对照组，n＝3人；LR代表锂盐反应组，n＝3人；NR代表锂盐不反应组，n＝3人。
图3为根据本发明的实施例提供的在夜相和昼相的强迫游泳实验(FST)中野生型小鼠和Syt7 KO小鼠的静止不动时间。图3中分别给出了Syt7KO小鼠静止时间显示昼夜节律波动以及Syt7KO小鼠持续的静止时间缩短。图3中示出的灰色背景代表夜相，白色背景代表昼相；饼状图显示Syt7KO小鼠表型分布比例，n＝28。
图4为根据本发明的实施例提供的Syt7KO小鼠存在行为学缺陷的结果图。其中图4中A为在夜相和昼相的悬尾实验(TS)中，野生型小鼠和Syt7 KO小鼠的静止不动时间结果，n＝12。图4中B为在夜相和昼相的习得性无助实验(LH)中，野生型小鼠和Syt7 KO小鼠的逃离失败次数，n＝8。图4中C为在夜相和昼相的糖水偏好实验(SPT)中显示出糖水偏好的野生型小鼠和Syt7 KO小鼠的比例，n＝8。图4中D为在夜相和昼相的明暗箱测试实验(LDB)中，小鼠在明亮箱中停留的时间，其中黑夜相n＝10，白昼相n＝12。图4中E为Syt7 KO小鼠的精神分裂测试的结果。
图5是根据本发明的实施例提供的精神药物奥氮平和锂盐对Syt7 KO小鼠行为异常的治疗效果。其中图5中A和B是在夜相(A)和昼相(B)的强迫游泳实验(FST)中，腹腔注射奥氮平(OLZ)(0.2-1.0mg/kg)对小鼠静止时间的影响。
图6根据本发明的实施例提供的大剂量奥氮平(1.0mg/kg)注射对Syt7 KO小鼠行为异常的治疗效果。其中图6中A代表对LH测试逃跑失败次数的影响结果，B代表对SPT测试中糖水偏好的影响结果，C代表对LDB测试中亮处滞留时间的影响结果。
图7是根据本发明的实施例提供的腹腔注射锂盐(30mg/kg)对Syt7 KO小鼠行为异常的治疗效果。其中图7中A示出了对FST实验中小鼠静止时间的影响，B示出了对LH测试逃跑失败次数的影响，C示出了对SPT测试中糖水偏好的影响，D示出了对LDB测试中亮处滞留时间的影响，这些实验中n＝8，采用Student’s t-test；*P<0.05；error bars,s.e.m.。
图8是根据本发明的实施例提供的BD病人血浆中Syt7 mRNA的水平检测结果，所示出的为20个BD病人和11个健康对照组的Syt7mRNA的定量分析结果。图8中B为BD-I型(n＝11)和BD-II型(n＝5)病人Syt7mRNA的水平。
图9是根据本发明的实施例提供具有不同BD患病类型、BD家族史、药物治疗和是否存在精神错乱的BD病人血浆中Syt7 mRNA的水平检测结果图。其中图9中A示出了BD-I型(n＝11)和BD-II型(n＝5)病人Syt7mRNA的水平；B示出了有(n＝7)无(n＝10)并发症(精神错乱)的BD病人Syt7mRNA水平的比较结果；C示出了有(n＝5)无(n＝9)BD家族史的BD病人Syt7mRNA水平的比较结果；D代表有(n＝14)无(n＝3)治疗经历的BD病人Syt7mRNA水平的比较结果；上述结果均采用Student’s t-test；*P<0.05；**P<0.001；error bars,s.e.m.。
图10是根据本发明的实施例提供的诊断双向情感障碍或判断双向情感障碍预后效果的系统的示意图。
具体实施方式
下面详细描述本发明的实施例，需要说明的是，所描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。
在本发明的一个方面，本发明提供了一种用于双向情感障碍的生物标志物，所述生物标志物包括Syt7基因和/或其表达产物。本文中“生物标志物”在本领域中具有普遍的含义，是可以表示生物分子和/或其可检测部分，并通过对其进行定性或者定量评估来获得预测性 信息或者诊断性信息等。例如，可以通过对受试者中相应生物标志物进行检测，来表征受试者关于给定疾病或者病症的状态。生物标志物可以是基因、蛋白或者多肽等等。
本发明还提供了一种Syt7基因和/或其表达产物在制备药物中的用途，所述药物用于治疗双向情感障碍和/或其并发症。根据本发明的实施例，Syt7基因的表达产物可以作为蛋白药物，通过给予双向情感障碍患者或其并发症患者适量的蛋白药物，提高Syt7基因表达产物在体内含量，从而可以用于治疗双向情感障碍或者并发症。
本发明还提供了一种诊断受试者是否患有双向情感障碍的方法，包括对来自所述受试者的生物样品中Syt7基因和/或其表达产物进行检测。
本文中，当提到受试者或者患者时，通常是指人类，当然还可以根据需要，包括非人类动物，优选为温血动物，更优选为胎生动物，更优选为哺乳动物。例如，非人类灵长类动物、啮齿动物、犬科动物、猫科动物、马科动物、绵羊、猪等等。
在本发明的另一方面，本发明还提供了一种诊断双向情感障碍或判断双向情感障碍预后效果的系统，如图10所示，包括：获得装置，所述获得装置用于获得生物样品中Syt7基因或其表达产物的量；判断装置，所述判断装置与所述获得装置相连，所述判断装置用于基于所述生物样品中Syt7基因或其表达产物的量，诊断双向情感障碍或判断双向情感障碍预后效果。
根据本发明的实施例，所述判断装置进一步包括：所述生物样品中Syt7基因或其表达产物的量低于正常样本中Syt7基因或其表达产物的量，是所述生物样品患有双向情感障碍的指示；或所述生物样品中Syt7基因或其表达产物的量至少不低于正常样本中Syt7基因或其表达产物的量，是所述双向情感障碍患者预后效果良好的指示。根据本发明的优选实施例，所述生物样品中Syt7基因或其表达产物的量至少低于正常样本中Syt7基因或其表达产物的量的0.5倍，优选1倍，是所述生物样品患有双向情感障碍的指示。
本文中，“样品”或者“生物样品”可以包括来自受试者的任意生物样品。包括但不限于全血、血浆、血清、红细胞、白细胞(例如，外周血单核细胞)、唾液、尿、大便(即粪便)、眼泪、汗液、皮脂、乳头抽吸物、导管灌洗物、肿瘤渗出物、滑液、脑脊液、淋巴样液、细针抽吸物、羊水、任何其它体液、细胞裂解液、细胞的分泌产物、炎症液。优选可以为血浆、血清、或细胞沉淀物。
本文中，术语“双向情感障碍”在本领域也常称为双相情感障碍。所提到的双向情感障 碍包括I型双向情感障碍(也称为BD-I型)和II型双向情感障碍(也称为BD-II型)以及混合型。Syt7基因及其表达产物优选可以作为I型双向情感障碍的生物标志物，用于指示是否患有I型双向情感障碍以及药物预后治疗等等。
本文中，I型双向情感障碍是典型的重燥狂重抑郁，即抑郁症和躁狂症的严重程度相同，都很重。而II型双向情感障碍是典型的轻躁狂重抑郁，即躁狂症轻，程度明显低于抑郁症发病程度。而混合型主要是指躁狂症状和抑郁症状在一次发作中同时出现，临床上较为少见。
本文中，所提到的双向情感障碍并发症是指由双向情感障碍疾病在发展过程中所引起的疾病，这种并发症可以表现为与双向情感障碍伴随，或者表现为不同于双向情感障碍的其他病症。例如可以为I型双向情感障碍共患强迫症(OCD)，该症状通常伴随着社交恐惧症、焦虑(回避)型人格障碍以及较少的精神病症状等。
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1 Syt7鉴定为神经精神疾病-类似行为的候选风险因子
为了有效鉴定BD病人情绪异常的贡献因素，我们选择性观察了BD病人来源iPSC分化神经元中一些基因的表达和功能。同时考虑到BD病人的一个重要特征是约有40％的BD病人同时患有胰岛素/葡萄糖代谢疾病(参考文献Ruzickova M,Slaney C,Garnham J,&Alda M(2003)Clinical features of bipolar disorder with and without comorbid diabetes mellitus.Canadian journal of psychiatry 48(7):458-461，文献Hajek T,McIntyre R,&Alda M(2016)Bipolar disorders,type 2 diabetes mellitus,and the brain.Current opinion in psychiatry 29(1):1-6，以及文献Wysokinski A,Strzelecki D,&Kloszewska I(2015)Levels of triglycerides,cholesterol,LDL,HDL and glucose in patients with schizophrenia,unipolar depression and bipolar disorder.Diabetes&metabolic syndrome 9(3):168-176)。我们猜想，脑中的关键分子通路缺陷会导致行为症状，那么这些缺陷发生在胰岛中会不会引起胰岛素代谢疾病，从而引起两者并发症状。
基于上述猜想，利用关键词胰岛素(糖尿病)和突触调研了GeneCards数据库，结果发 现有97个基因同时出现在胰岛素代谢和突触功能中。通过NCBI文献检索(www.ncbi.nlm.nih.gov/pubmed/)，从97个基因中筛选出18个可能在上述两个症状中起作用的基因。
然后利用此前建立的6例BD病人的iPSC和相应分化的神经元(参考文献Mertens J,et al.(2015)Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder.Nature 527(7576):95-99.)，从这些病人iPSCs分化的神经元中，利用RNA-seq和qRT-PCR手段发现18个基因中的11个，mRNA表达水平出现超过1.5倍的变化(如图1中A和B所示，具体所示出的纵坐标变化值可以表现为增加或者减少)。其中图1中A为18个候选基因在BD病人iPSC分化的海马神经元中转录组测序(RNA-seq)的结果；图1中B为18个候选基因在BD病人iPSC分化的海马神经元中实时荧光定量RT-PCR的结果。其中，HC代表健康对照组，n＝4人；BD-I代表I-型BD病人，n＝6人，其中图1中A和B图横坐标每个基因对应的两列柱状图从左到后分别代表健康对照组合I-型BD病人的数据。
随后，利用shRNA病毒敲减了小鼠DG区的这11个基因，随后进行强迫游泳实验(FST)，分析了小鼠的静止时间，小鼠静止时间的指标可以显示小鼠的情感绝望程度，时间越长，绝望情绪越严重。其结果如图1中C所示。图1中C图示出了候选基因被敲减(KD)后FST测试中小鼠静止时间的结果，n＝10，采用的t检验方法(Student’s t-test.*P<0.05；error bars,s.e.m.)。
结果表明，和野生组相比较，Syt7敲减小鼠的静止时间明显减少，其它基因的敲减则没有类似明显的变化。由此，推测Syt7有可能是行为异常的候选风险因子。
实施例2 Syt7缺陷诱导小鼠产生波动性的行为异常
为了系统研究Syt7在脑精神疾病-类似行为中的作用，首先独立研究了两类不同来源的iPSC分化神经元中BD病人体内Syt7的表达情况。其中图2中A和B示出了在文献Mertens J,et al.(2015)Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder.Nature 527(7576):95-99中所记载的LR和NR病人来源的海马神经元中Syt7的表达情况，其中LR代表对lithium(锂盐)起反应的iPSC分化神经元，NR代表对lithium不起反应的iPSC分化神经元。图2中C示出在了文献Stern S,et al.(2017)Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients'responsiveness to lithium.Molecular psychiatry中所记载的iPSC分化的海马神经元中Syt7表达情况。其结果表明，在这两类神经元中，qRT-PCR和免疫蛋白印迹分析检测同健康对照组的差异，结果均表现为Syt7的表达下降。证实了在不同亚群的BD病人中存在Syt7缺陷。
我们随后检测了Syt7 KO小鼠(即Syt7基因敲除小鼠)在FST测试的表现。我们发现，和同窝的野生型小鼠比较，几乎30％的Syt7 KO小鼠，无论是在夜相(ZT 12-24)或昼相(ZT 0-12)都表现出更短的静止时间(如图3中所示出的持续狂躁结果，英文可以用Manic-like表示)。有趣的是，超过60％的KO小鼠表现出波动性的行为异常表型，即在夜相静止时间更短，昼相静止时间更长(如图3中所示出的双极波动结果，英文可以用Fluctuation表示)。
随后进行的行为学实验，集中在这些出现昼夜交替表型的Syt7KO小鼠上。我们进行了悬尾实验(TS)，分析了静止不动时间，小鼠静止时间的指标可以显示小鼠的情感绝望程度，时间越长，绝望情绪越严重。实验结果发现Syt7KO小鼠同野生型比较，在夜相小鼠表现出显著简短的静止时间，在昼相更长的静止时间，如图4中A所示(灰色背景部分代表夜相，白色背景代表昼相，其他附图也采用相同的表示方式)。
考虑到FST/TS实验无法代表人类疾病的所有表征，我们分别进行了习得性无助测试(LH)和糖水偏好测试(SPT)实验。其中LH和抑郁有关，LH实验中小鼠的逃跑失败的次数是检测动物因外界压力而抑郁的一个指标，逃跑失败次数越多，抑郁越明显。SPT和快感缺乏有关，小鼠偏好糖水的比例可以作为检测小鼠的快感缺失程度的指标，更高的糖水偏好比例，说明快感增强。如图4中B和C所示，和野生型小鼠作比较，夜相中Syt7KO小鼠更躁狂(LH测试表现更少的逃生失败次数)和SPT测试中更多的快感获得；而在昼相中，Syt7KO小鼠总是展示出相反的表现。
由于BD病人通常会伴有焦虑的临床症状，接下来，进行了明暗箱(LDB)的测试观察到Syt7KO小鼠有焦虑类似的行为。结果表明，同野生型小鼠比较，Syt7KO小鼠在夜相中表现出减少的焦虑行为，而在昼相中表现增强的焦虑，如图4中D所示。
同时，为了弄清Syt7KO小鼠行为的异常是永久性的还是只在特定的时间段发生，运用旷场实验对小鼠进行24小时的监测，结果发现Syt7KO小鼠在夜相活动上升，但在昼相活 动下降，这与FST实验和悬尾实验得到的结论是相对应的。重要的是，Syt7KO小鼠活动的变化在夜相和昼相中是持续存在的，说明小鼠的情绪异常是持久出现的。
另外，由于临床研究发现，BD病人常表现出精神错乱的症状，因此利用PPI实验(前脉抑制实验)观察Syt7KO小鼠的精神错乱-类似行为。PPI测试是经典的用于检测动物精神错乱的行为范式。在PPI测试中，PPI比例越低，说明小鼠的精神错乱越严重。如图4中E所示，和野生型小鼠比较，无论是在夜相还是在昼相，Syt7KO小鼠总是显示更少的PPI比例，其不受光照影响，说明Syt7KO小鼠中持续存在类似精神病的行为；而且Syt7KO小鼠表现出类似的声致惊厥反应。
综上，我们的结果显示LR和NR两类病人来源的iPSC分化神经元都存在Syt7缺陷；更重要的是，Syt7KO小鼠表现出行为异常，所展现的夜/昼周期特征是双极-类似行为的行为异常波动所特有的。
实施例3 情绪稳定剂处理Syt7KO小鼠
为了进一步确定Syt7KO小鼠行为异常和BD表征的关系，我们用临床上和临床前治疗BD病人的两种药物，奥氮平(olanzapine，OLZ)和lithium处理Syt7KO小鼠，观察动物行为。
首先用非典型抗精神病药物奥氮平(olanzapine，OLZ)处理Syt7KO小鼠，并观察剂量依赖关系(所用到的剂量分别为0.2，0.5和1.0mg/kg)(采用ANOVA统计方法)。如图5中A和B所示，在FST测试中，和非处理组比较，药物处理组的Syt7KO小鼠，在中等剂量的奥氮平作用下足够改变行为异常(即，夜相相对较短的静止时间被反转)；进而，高剂量奥氮平处理延长了昼相的静止时间。另外，采用低剂量奥氮平处理，减少了Syt7KO小鼠在白昼相的静止时间这不同于高剂量的结果。不受理论限制，这可能与奥氮平在治疗BD病人中的抗抑郁效果相关。
继而采用LH/SPT/LDB的行为学范式，检测高剂量奥氮平处理(1.0mg/kg)对Syt7KO小鼠行为异常的效果。如图6中A、B和C显示，无论是在夜相还是昼相，高剂量奥氮平处理都缓解了Syt7KO小鼠的抑郁状态，同非处理组的KO小鼠相比，显著增加了LH测试中的逃跑次数，减少了蔗糖偏好，减少了LDB测试中在白箱中的时间。除此之外，奥氮平处理WT小鼠也得到了和Syt7KO小鼠类似的结果。
随后测试了临床治疗BD的药物lithium对Syt7KO小鼠行为异常的影响。在FST实验静止时间的测试中，无论是在夜相或是昼相，30mg/kg Li 2CO 3的处理对WT和Syt7KO小鼠均不起作用，如图7中所示。但是，在LH和SPT实验中，Li处理的WT和Syt7小鼠均表现出改善的抗抑郁效果，即无论是在黑夜相或是白昼相，同非处理对照组比较，表现增加的逃跑次数和减少的糖水偏好，如图7中B和C所示。进而，在LDB测试中，Li处理对WT没有作用，但是改变了Syt7KO小鼠的行为，使它们在白箱的停留时间减少，该改变无论在黑夜相和白昼相都会发生，如图7中D所示。
综上所述，结果显示临床治疗BD病人的药物对Syt7KO小鼠的行为异常有明显效果。
实施例4 BD病人血浆中Syt7表达的诊断
最后，为了观察BD病人中Syt7的情况是否同iPSC分化神经元中的缺陷相吻合，我们分析了BD病人血浆中的mRNA水平。我们搜集到20个BD病人样本和11个年龄和性别相匹配的健康对照组(HC)，分离血浆。然后用qRT-PCR方法分析了血浆中Syt7 mRNA的表达水平。结果显示，和HC组比较，BD组Syt7mRNA水平显著减低(如图8所示)，表明BD病人中确实存在Syt7缺陷。
然后将BD病人按照年龄，性别和病理进程严重程度进行分组。总体上，同HC组比较，大部分BD病人的Syt7mRNA水平都表现出下降趋势；我们注意到，30岁以上的病人Syt7mRNA水平减少不明显。尽管样本量偏少，但结果仍然提示Syt7的缺陷可能在年轻成人中更明显。我们进一步将BD病人按照类型，BD家族史，药物治疗和是否存在精神错乱进行了分组和分析。我们发现，同HC组比较，BD-I型和BD-II型病人的血浆Syt7mRNA水平均显著减少(如图9中A所示)。
进而，同HC组比较，没有精神错乱和BD家族史病人的Syt7mRNA水平减少很明显，而那些有精神错乱症状或BD家族史的病人存在Syt7mRNA减少的趋势(如图9中B和C所示)。值得指出的是，未经治疗组的病人表现出显著Syt7mRNA水平减少，尽管样本量小；治疗组的病人Syt7mRNA有所恢复，虽然同HC组比较仍是减低(如图9中D所示)。
以上实验结果表明，Syt7信号通路在BD的情绪循环中起关键作用，靶向Syt7上下游信号分子的诊断和治疗方法的开发将会对BD的诊疗带来曙光。
此外，术语“第一”、“第二”仅用于描述目的，而不能理解为指示或暗示相对重要性 或者隐含指明所指示的技术特征的数量。由此，限定有“第一”、“第二”的特征可以明示或者隐含地包括至少一个该特征。在本发明的描述中，“多个”的含义是至少两个，例如两个，三个等，除非另有明确具体的限定。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (12)

  1. 一种用于双向情感障碍的生物标志物，其特征在于，所述生物标志物包括Syt7基因和/或其表达产物。
  2. Syt7基因和/或其表达产物在制备药物中的用途，所述药物用于治疗双向情感障碍和/或其并发症。
  3. 根据权利要求2所述的用途，其特征在于，所述药物能够使得所述Syt7基因的表达量增多。
  4. 一种双向情感障碍细胞模型，其特征在于，与野生型细胞相比，所述双向情感障碍细胞模型中含有的Syt7基因和/或其表达产物的量降低。
  5. 一种双向情感障碍动物模型，其特征在于，与野生型动物相比，所述双向情感障碍动物模型中含有的Syt7基因和/或其表达产物的量降低。
  6. 根据权利要求5所述的双向情感障碍疾病动物模型，其特征在于，所述动物包括选自小鼠、大鼠或者灵长类动物中的至少一种。
  7. 一种筛选用于治疗双向情感障碍的药物的方法，其特征在于，包括：
    将候选药物施用于权利要求4所述的双向情感障碍细胞模型或者权利要求5或6所述的双向情感障碍动物模型；
    筛选使得Syt7基因或其表达产物的量上升的候选药物，或者筛选使得双向情感障碍症状减轻的候选药物，作为所述用于治疗双向情感障碍的药物。
  8. 一种试剂盒，其特征在于，包括特异性检测Syt7基因或其表达产物的试剂。
  9. 根据权利要求8所述的试剂盒，其特征在于，所述试剂包括引物和/或探针。
  10. 一种诊断双向情感障碍或判断双向情感障碍预后效果的系统，其特征在于，包括：
    获得装置，所述获得装置用于获得生物样品中Syt7基因或其表达产物的量；
    判断装置，所述判断装置与所述获得装置相连，所述判断装置用于基于所述生物样品中Syt7基因或其表达产物的量，诊断双向情感障碍或判断双向情感障碍预后效果。
  11. 根据权利要求10所述的系统，其特征在于，所述判断装置进一步包括：
    所述生物样品中Syt7基因或其表达产物的量低于正常样本中Syt7基因或其表达产物的量，是所述生物样品患有双向情感障碍的指示；或
    所述生物样品中Syt7基因或其表达产物的量至少不低于正常样本中Syt7基因或其表达 产物的量，是所述双向情感障碍患者预后效果良好的指示。
  12. 一种诊断受试者是否患有双向情感障碍的方法，其特征在于，包括对来自所述受试者的生物样品中Syt7基因和/或其表达产物进行检测。
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