PTEN-端粒互作调控卵巢衰老机制研究

Premature ovarian ageing (POA) underpins infertility, menopause and ovarian cancer. Although hormonal imbalance is involved, including estrogen deficiency, the molecular mechanisms mediating POA remains largely elusive. Recent studies indicate that the tumor suppressor phosphatase and tensin homolog (PTEN) plays a fundamental role in suppressing ovarian function including follicular activation. Our data showed that PTEN inhibits the maintenance activity of the chromosome ends (telomeres), suggesting that PTEN inhibition of ovarian reproduction involves telomere remodeling. We further found that telomere shortening underpins POA induced by estrogen deficiency. Thus, we hypothesize that telomere remodeling constitutes a central mechanism controlling ovarian cell ageing which is governed by dual regulations of estrogen and PTEN. We will utilize the Aromatase (estrogen synthase) gene knockout mice to investigate the mechanisms of estrogen deficiency-induced POA.

卵巢早衰（POA）会引起不孕、绝经甚至卵巢癌。体内激素紊乱（如雌二醇缺乏）会导致POA，但POA发生的分子机理目前仍不清楚。最近研究发现，肿瘤抑制因子—同源性磷酸酶-张力蛋白（PTEN）在抑制卵巢卵泡形成和排卵中发挥重要作用。PTEN是如何抑制卵泡激活，它的下游效应分子有哪些，这些问题我们还没有答案。我们最近发现，PTEN能够直接抑制卵巢卵泡中颗粒细胞的端粒酶活性，而端粒酶是一种能够维持细胞染色体末端（端粒）长度的酶，表明PTEN对卵巢功能抑制作用很有可能是通过抑制端粒酶以及端粒重塑这一机制。我们推测，端粒重塑在控制卵巢卵泡形成和细胞衰老中可能起核心作用，并且这一过程受雌二醇和PTEN双重调节。我们将进一步探讨PTEN对端粒酶及端粒重塑的机理，并使用Aromatase（雌激素合成酶）基因敲除小鼠，研究雌激素缺乏对PTEN和端粒引起卵巢颗粒细胞衰老及卵巢早衰的作用机制。