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中国科学技术大学分子细胞遗传学实验室
Molecular&Cell Genetics Laboratory
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Bioinformatics
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研究方向一:肿瘤细胞遗传学
研究背景
肿瘤与染色体数目异常密切相关:
1. 75%以上的人类肿瘤都是非整倍体;
2. 非整倍体细胞的出现早于肿瘤的出现(Nat Genet. 2004, 36(11): 1159-61 & 1144-45);

3. 肿瘤中非整倍体细胞的比例与肿瘤的恶化进程、转移风险成正比(Mitelman等,1997);

4. 非整倍体肿瘤的治疗效果远差于整倍体肿瘤;
5. 非整倍体肿瘤的复发率远高于整倍体肿瘤,且与肿瘤中非整倍体细胞的比例成正相关
 
存在问题

1. 染色体异常的肿瘤细胞是如何产生的?即是通过多极有丝分裂还是双极有丝分裂产生的?细胞分     裂过程中的染色体落后能否导致非整倍体细胞的发生?

2. 细胞分裂的后期和末期是否存在监控染色体分离的机制?如果有,这个机制的阻止分子组成是什     么?它如何防止非整倍体子细胞的形成?
3. 非整倍体细胞的命运(死亡、细胞周期停滞或细胞分裂)是如何决定的?我们能否通过控制非整     倍体细胞的命运来预防和治疗肿瘤?
 
正在进行的工作
1. 非整倍体肿瘤细胞的发生途径及机制研究
2. 非整倍体细胞命运决定的分子机制
3. 早期胚胎发育过程中非整倍体细胞的产生途径和命运
4. 卵泡细胞染色体分离异常与卵子发生
 
研究方向二:生殖分子生物学
研究背景
染色体非整倍体严重危害人类生殖健康
1. 人类自发流产发生率10-15%,且随母亲年龄增大显著升高,约1/3自发流产归因于非整倍体
New Engl J Med 351:19, 2004
2. Down's综合征(21号染色体三体)发病率随母亲年龄增大显著升高
New Engl J Med 351:19, 2004
 
正在进行的工作

1. 卵泡形成和募集的分子调控机制
2. 减数分裂启动和正常进行的分子调控
3. 干细胞向生殖细胞的诱导分化
4. 人类生殖相关疾病致病因子的遗传筛查及功能研究

研究方向三:Meiotic checkpoints and their regulation: DNA damage on fates of spermatocytes and oocytes

To achieve accurate homologus chromosome pairing, synapsis, recombination and segregation, hundreds of programmed DNA double strand breaks (DSBs) must occur and then be repaired during the prophase of meiosis. Failure to repair the DSBs results in meiotic arrest at zygotene or pachytene stage in male and oocyte loss during primordial follicle assembly in female, indicating the presence of different cell cycle checkpoints between the sexes. We try to understand the regulation mechanisms of the checkpoints during spermatogenesis and oogenesis by using gene modified mice.

研究方向四:Identification of genetic mutations causing human male infertility by disrupting meiosis

Meiosis is an essential process of spermatogenesis, anomalies of which may cause spermatogenesis failure and consequently infertility. Hundreds of genes have been reported to cause infertility by disrupting meiosis after mutated in mice. However, only several of them have been detected mutated in infertile human males. No classification and low number of cases, as well as inefficient technology for the detection of mutants in patients are accused for the failure to find mutations causing meiotic abnormalities. We are trying to identify such mutations by genome-wide exon sequencing of thousands of patients with non-obstructive azoospermia classified according to their meiotic abnormalities.

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