臺灣人體生物資料庫子宮內膜異位症之生物標誌研發

  • 2016-03-30
  • TES

Endometriosis occurs when shed endometrium from the female reproductive tract grows outside the uterus, which might cause infertility and dysmenorrhea. The pathophysiology in endometriosis—abnormal tissue growth, invasion, and adhesion formation—are similar to those seen in tumorous tissues. The aetiology of endometriosis is not well understood. Several factors such as immunological, genetic and environmental factors may involve the susceptibility to develop endometriosis. In the very recent years, evidence has emerged that endometriosis may be an epigenetic diseases in which microRNA may involve. The microRNAs acting as agents of the RNA interference pathway have been implicated in the regulation of a variety of cellular processes, and even the pathogenesis process of human diseases including endometriosis. According to BNHI statistics every year there are 49,000 new cases of endometriosis has been registered in Taiwan. Combined with annual 240,000 patient visits, the direct and indirect cost estimated for this disease is about USD 1.37 billion. Each year, about one third of women who received in vitro fertilization (IVF) treatment have been diagnosed of having endometriosis at Taipei Medical University Hospital. The causes and mechanisms of endometriosis remain unclear so far; moreover, the clinical diagnosis and treatment of endometriosis have lots of problems including: the diagnosis still needs invasiveness laparoscopy and the treatment which based on surgical removal of endometrial tissue and hormone medication, but both methods all have defects such as relapse of disease or drug side effect. Our current studies based on cDNA microarray, we have discovered several genes including: integrins/cell adhesion molecules, metalloproteinases (MMP14), cathepsins, estrogen receptors, VEGFs, aromatase, EGFR, MAPK and cytokines (IL-6, SDF-1 and CXCR4). By the proteomic approach, we have identified Alpha 1-antitrypsin (a1-AT) as a potential biomarker. Therefore, in this project we will combine functional genomics, microRNA, proteomic approach and clinical research to study the gene expression pattern, mechanism and signal transduction of endometriosis, and verify genes that would alter the cell growth and invasiveness of endometrial cells. Furthermore, next-generation sequencer would be used to analyze the genomic pattern of patients who have family history of endometriosis as well as epidemiological study of this disease.

The specific aims of this project:
1: To build a biorepository and information signaling and screening of biomarkers for endometriosis
2: To identify and validate the endometriosis-associated biosignatures (microRNA, endometriosis-related gene and protein.)
3: To investigate the endometriosis-associated genetic polymorphism and environmental risk factors in Taiwan
4: To develop the diagnostic kit or chip for early and quick diagnosis of Endometriosis

In 2013-14, we used the DNA microarray to study patterns of gene expression. According to DNA microarray, several genes including integrins/cell adhesion molecules, metalloproteinases (MMP 14), cathepsins, estrogen receptors, VEGFs, aromatase, EGFR, MAPK and cytokines (IL-6, SDF-1 and CXCR4) etc. were found to be up-regulated in patients with endometriosis compared with the controls. On the contrary, Tensin 1, MMP 14, Caveolin 2, Neuritin 1, ATP 2A3 E-cadherin and CD34 were found significant down-regulated in GnRHa-treated group compared with the controls. The findings were also confirmed by immunohistochemitry. Moreover, 2) SNP analysis also demonstrated that MMP14 (rs743257), MMP9 (rs3918242) and TIMP-1 (rs4898 Phe124Phe) gene polymorphisms were associated with endometriosis. Besides, 3) enhanced Osteopontin (OPN) expression was verified in the endometriotic tissue which increased the cell migration and cell proliferation by NF-kb signaling pathway in the endometriotic cells. In addition, nine candidate gene pairs of target and host genes with related microRNA were also identified. These results indicated that these biomarkers may be the potential biosingnatures for early detection and follow-up of this disease. Therefore, in this project we will combine functional genomics, microRNA, proteomic approach and clinical research to study the mechanism and signal transduction of endometriosis, and verify genes that would alter the cell growth and invasiveness of endometrial cells. Furthermore, next-generation sequencer would be used to analyze the genomic pattern of patients who have family history of endometriosis as well as epidemiological study of this disease.