兰州大学机构库 >第二临床医学院
外泌体治疗糖尿病大鼠勃起功能障碍的相关研究
Alternative TitleCell-Derived Exosomes Ameliorate Erectile Dysfunction in a Rat Model of Type 2 Diabetes
李彦佑
Subtype硕士
Thesis Advisor董治龙
2023-05-17
Degree Grantor兰州大学
Place of Conferral兰州
Degree Name医学硕士
Degree Discipline外科学
Keyword细胞 cell 外泌体 exosome 糖尿病 diabetes mellitus 勃起功能障碍 erectile dysfunction
Abstract

研究背景与目的:男性糖尿病(Diabetes Mellitus,DM)患者中,糖尿病相关勃起功能障碍(Diabetic Erectile Dysfunction, DED)是常见并发症之一,严重影响其生活质量,且当前治疗方式的效果不甚满意。基于此现状,众多学者提出利用具有修复功能的干细胞对此种难治性疾病进行干预以期取得良好效果。许多研究证明干细胞在发挥治疗作用时依靠其分泌功能,其中,外泌体是其发挥分泌功能的主要分泌物之一。外泌体因包含各类生物活性分子且十分稳定,在疾病治疗方面具有强大潜力。在DED治疗研究中,使用不同种类干细胞来源的外泌体干预DED大鼠获得了良好的疗效。在本项目中,研究者使用meta分析对目前使用细胞外泌体(Exosomes derived from  Cells, EC)对糖尿病大鼠模型的干预进行系统性评价,以及使用生物信息学分析对细胞外泌体治疗DED相关分子机制进行初步探索,证明其治疗作用,为使用非侵入性且具有成本效益的干细胞外泌体治疗DED的可能性提供理论基础。

方法:第一部分:计算机检索数据库Pubmed、Scopus、web of science、CNKI、维普、万方等数据库,检索时间从建库至2023.02,自由词及主题词为外泌体、细胞外囊泡、糖尿病勃起功能障碍,根据纳入与排除标准,筛选文献,提取有效数据,使用ReVMan5.3软件分析各类干细胞外泌体在治疗DED大鼠模型的阴茎海绵体体内压力(Intracavernous Pres-

Sure, ICP);内皮型一氧化氮合酶(Endothelial Nitric Oxide Synthase,eNOS)含量;神经元型一氧化氮合酶(Neuronal Nitric Oxide Synthase,nNOS)含量;阴茎平滑肌组织含量 ,以评估治疗的有效性。第二部分: 从GEO数据库中获取糖尿病勃起功能障碍大鼠阴茎组织所获取的基因芯片表达谱,利用相关软件分析5个糖尿病勃起功能障碍大鼠阴茎组织样本和5个健康大鼠样本的GSE2457数据集的差异基因(Differential gene expression,DEG),从不同外泌体数据库中获取不同干细胞来源外泌体所测序得到的miRNA,并进行相应的靶基因预测,对筛选出的差异基因与预测靶基因进行关联性分析。最后,对这些基因进行生物过程、组织以及信号通路的富集,观察其参与的生理过程、组织特异性及相关信号通路。

 

结果:

第一部分:共纳入7篇文献,纳入实验动物共96例,其中实验组48例,对照组48例。结果显示,外泌体能够有效恢复糖尿病相关勃起功能障碍大鼠的阴茎海绵体内压ICP,增加eNOS、nNOS的含量,增加阴茎组织平滑肌的含量。第二部分:通过对组织差异基因的分析,共筛选出93个DEGs,其中包含42个上调基因以及51个下调基因,通过检索相关数据库及查阅相关文献,干细胞来源外泌体的测序结果为:let7a5p、let7b5p、let7f5p、let7g5p、let7i5p、mir10a5p、mir10b5p、mir215p、mir26a5p、mir27a3p、mir30a5p、mir30d5p、mir99a5p、mir148a3p、mir151a3p,进行靶基因预测后共得到2083个基因,最后与差异基因进行关联性分析后最终得到10个相关基因,分别为:B4GALT1、COL1A2、CPEB1、FGF5、GPCPD1、GREM1、LPL、NPR3、PDK4、TFRC,通过功能的富集,这些基因与血管生产成、循环系统过程以及机体组织细胞对于有机氮的效应有关系,特异的作用组织为平滑肌组织,信号通路主要作用于NF-κB信号通路。

结论:使用外泌体针对糖尿病相关勃起功能障碍进行干预可以阴茎海绵体内压ICP,增加eNOS、nNOS的含量,增加阴茎组织平滑肌的含量。外泌体针对糖尿病相关勃起功能障碍的干预可能是将相关miRNA导入组织细胞内从而发挥作用,且与B4GALT1、COL1A2、CPEB1、FGF5、GPCPD1、GREM1、LPL、NPR3、PDK4、TFRC有关。

关键词:细胞,外泌体,糖尿病,勃起功能障碍

Other Abstract

Background: Diabetic erectile dysfunction (DED) is one of common complications in men with diabetes, which deeply affects patients' quality of life, and the effects of current therapy are not satisfactory. Currently, many scholars proposed that patients can be benefited of using the stem cell. many studies have shown that stem cells exert their functional benefits through their secretory function. exosomes are one of secretions from stem cell, which play a secretion function. Owing to its bioactive molecules and stability, exosomes have strong potential for disease treatment. During the process of treatment in DED, Exosomes derived from different stem cells hold good promise in rats with DED. In the present project, Meta-analysis was used to conduct systematic review of the therapy of Exosomes derived from Stem Cells to diabetic erectile dysfunction. Using bioinformatic methods, we performed an initial exploration of the molecular mechanism of the theraputic effects of Exosomes derived from stem Cells.

  Method: Part I :Pubmed、Scopus、web of science、CNKI、VIP、Wanfang were systematic searched  from inception to march 2023,subject words and free words include: exosome、extracellular vesicle、nanovesicle、diabetic erectile dysfunction. Two investigators    screened the literature and extracted data independently according to the inclusion and exclusion criteria. All analyses were conducted using RevMan5.3 software to assess the relative efficacy of therapies. Part II: Gene expression profiles of DED were extracted from GEO database. Relative software was used to analysis the Differential gene expression in group GSE2457 datasets, which includes 5 experimental samples and 5 control samples. the corresponding target genes of exosome miRNAs were predicted using the web-based miRNA- target gene prediction tool,then we analyze the correlation of the differential genes and predicting target genes. Finally, functional enrichment was analyzed by us to confirm related physiological processes, tissue-specificity and signaling pathway.

Results: Part I: 7 original articles involving a total of 96 rats were included; among these, 48 cases were in the experimental group and 48 cases in the control group. Exosomes derived from stem cells can improve ICP and increase the content of eNOS;nNOS and smooth muscle. Part II: In group GSE2457 datasets, A total of 93 overlapping DEGs were screened, including 42 up-regulated genes and 75 down-regulated genes. The miRNA of exosomes derived from stem cells were identified through database and reference searching, which is inclued:let7a5p、let7b5p、let7f5p、let7g5p、let7i5p、mir10a5p、mir10b5p、mir215p、mir26a5p、mir27a3p、mir30a5p、mir30d5p、mir99a5p、mir148a3p、mir151a3p. After target-genes predicting, we have found 2083 genes. Then we analyzed the correlation of the differential genes and predicting target genes, and 10 genes were ended up with, which include:B4GALT1、COL1A2、CPEB1、FGF5、GPCPD1、GREM1、LPL、NPR3、PDK4、TFRC. After the enrichment analysis, we found that these genes are related to blood vessel development, circulatory system process and cellular response to organonitrogen compound. Tissue-specificity is in smooth muscle and the signaling pathway is main include NF-κB signaling pathway.

Conclusion:  Exosomes derived from cells can improve ICP and increase the content of eNOS;nNOS and smooth muscle. Exosomes derived from stem cells can improve ICP and increase the content of eNOS;nNOS and smooth muscle. The mechanism may be that the exosome imported miRNA into cells to play a role in treatment, which is related to B4GALT1、COL1A2、CPEB1、FGF5、GPCPD1、GREM1、LPL、NPR3、PDK4、TFRC.

Key word: cell    exosome     diabetes mellitus    erectile dysfunction

 

Subject Area泌尿外科学;男科学
MOST Discipline Catalogue医学 - 临床医学 - 外科学
URL查看原文
Language中文
Other Code262010_220200904101
Document Type学位论文
Identifierhttps://ir.lzu.edu.cn/handle/262010/536403
Collection第二临床医学院
Affiliation
兰州大学第二临床医学院
Recommended Citation
GB/T 7714
李彦佑. 外泌体治疗糖尿病大鼠勃起功能障碍的相关研究[D]. 兰州. 兰州大学,2023.
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