尿液是血液的滤液，不受稳态机制的调节，可以积累和收集全身各处产生的变化；跟踪式的无创收集方式能让尿液中与疾病相关的变化更早期，更灵敏，因此是寻找疾病生物标志物的良好来源。

第一部分，我们通过尿液蛋白质组学分析为发热待查患者提供线索和诊断依据。发热待查是不能确定病因的疾病，我们收集了符合要求的发热待查患者尿液和健康人尿液，利用液相色谱串联质谱对其进行分析，采用一对多的分析方法，即一个病人和一组健康人样本对比分析，鉴定差异蛋白以及其相关的生物学通路。结果发现，我们能从尿液中看到与发热有关的生物学通路，比如LXR/RXR 激活、FXR/RXR激活、急性期反应等，说明尿液可以明显区分疾病与健康状态；同时每个患者的分析结果都不同，凸显一对多分析的必要性。我们的结果初步说明，尿液蛋白质组学和一对多分析相结合，能为发热待查提供线索，也可能应用于任何未知疾病的探索。

第二部分，我们尝试用尿液蛋白质组学检测惊吓带来的改变。我们采用天敌气味和声音刺激两种方式相结合共同建立了大鼠惊吓模型，在惊吓前后采集尿液样本并进行蛋白质组学分析。结果发现，惊吓后和惊吓前作比较，筛选出25个差异蛋白，这些差异蛋白富集到的生物学通路和神经递质运输、葡萄糖跨膜运输相关，这可能是惊吓引起的神经紧张状态表现。对每只大鼠进行了自身的前后对照分析发现，其中有1个蛋白被5只大鼠共同鉴定到，另外有19个蛋白被4只大鼠共同鉴定到，这些蛋白与神经、运动、代谢和血压的变化密切相关。其中包括谷氨酸—半胱氨酸连接酶催化亚基及其调节亚基，谷氨酸—半胱氨酸连接酶的功能可能和惊吓有关。这为研究惊吓的机制奠定了基础，为寻找治疗恐怖心理的药靶提供了新方法，同时充分说明了尿液的灵敏性，为尿液的探索开辟了新的领域。

第三部分，精神分裂症(SCH)是一组机制未明的精神系统慢性疾病，我们收集了10例首发未用药的SCH患者和9例健康对照(HC)人群临床样本，提取尿蛋白并进行LC-MS/MS分析，利用DAVID数据库和文献检索对差异蛋白进行功能分析。结果发现，SCH组对比于HC组，筛选到的35个差异蛋白中，有15个都被报道和SCH症相关，差异蛋白富集到的生物学通路，例如ephrin受体信号通路、长期突触增强（LTP）的正向调节等也和精神分裂症的致病机制以及一些治疗靶点相关。我们的结果初步证明了尿液蛋白质组学能够体现出精神分裂症和健康对照的差别，且这种差别不是随机产生的，我们能够从尿液中发现精神分裂症的鉴别诊断线索。

Urine is the filtrate of blood, which is not regulated by the steady-state mechanism and can accumulate and collect changes throughout the body. Tracking non-invasive collection methods can make disease-related changes in urine earlier and more sensitive, so it is a good source for finding disease biomarkers.

In the first part, we provide clues and diagnostic basis for patients with fever of unknown origin through urine proteomics analysis. Fever of unknown origin is a disease that cannot be determined. We collected urine samples from patients with fever of unknown origin and urine samples from healthy people, and analyzed urine proteins by liquid chromatography tandem mass spectrometry (LC-MS/MS). One-to-many comparison analysis was performed which means a patient and a group of healthy people samples were compared and analyzed to identify differential proteins and their related biological pathways. The results showed that we can see the biological pathways related to fever in urine, such as LXR / RXR activation, FXR / RXR activation, acute phase response, etc., indicating that urine can clearly distinguish between disease and health. At the same time, the analysis results of each patient are different, highlighting the necessity of one-to-many analysis. Our results preliminarily indicate that the combination of urine proteomics and one-to-many comparison analysis can provide clues for fever of unknown origin, and may also be applied to the exploration of any unknown disease.

In the second part, we tried to use urine proteomics to detect the changes caused by startle. The combination of natural enemy odor and sound stimulation were used to establish a rat model of startle. Urine samples were collected before and after startle and proteomic analysis was performed. The results showed that 25 differential proteins were identified after startle, and the biological pathways enriched in these differential proteins were related to neurotransmitter transport and glucose transmembrane transport, which may be the manifestations of nervous tension caused by startle. Before-after study in single rat was performed and found that there was one differential protein identified in common in five rats, in addition, 19 differential proteins were identified in common in four of five rats, and these proteins were associated with the change of nerve, motion, metabolism and blood pressure, which include catalytic subunits and regulatory subunits of glutamate-cysteine ligase, which related to the function of startle. These results laid the foundation for the research of startle mechanism, and to find medicine for the treatment of psychological terror target provides a new method. At the same time, it fully illustrates the sensitivity of urine and opens up a new field for the exploration of urine.

In the third part, schizophrenia is a group of chronic diseases of the mental system with unknown mechanism. Clinical samples were collected from 10 patients with first-episode untreated schizophrenia (SCH) and 9 healthy controls (HC). LC-MS/MS was used to analyze the extracted urinary proteins, and the differential proteins were analyzed by DAVID database and literature search. The results showed that, compared with HC group, 15 out of 35 differential proteins screened were reported to be related to SCH. Biological pathways enriched in differential proteins, such as ephrin receptor signaling pathway and positive regulation of long-term synaptic potentiation (LTP), were also related to the pathogenic mechanism and some therapeutic targets of schizophrenia. Our results preliminarily demonstrated that urine proteomics can show differences between schizophrenics and healthy controls, and that the differences are not random. The diagnosis clues of schizophrenia can be found from urine.