迈克尔斯泰西
RESEARCH副教授
电话: 757 683 2245
电子邮件: mstacey@bayankolsaatleri.com
地址: IRP 2, 4211 Monarch Way, Norfolk, VA, 23508
Education
- 博士后RESEARCH员: Followship in Cancer Pharmacology, University of Oxford, Engl和. 1994-97
- 博士后RESEARCH员: Fellowship in Clinical Genetics, 伯明翰大学, Engl和. 1991-94
- Ph.D.: Cancer predisposing syndromes in the Institute of Cancer 和 Genomic Sciences, 伯明翰大学. 1995
- B.S.: 动物学. 英国赫尔大学. 1981
官员迦勒Wyckoff称, Ph.D. 学生
RESEARCH描述
基因突变的癌症 IDH1 和 IDH2 genes are complex 和 may have differential carcinogenic potential dependent upon which IDH gene is mutated. Chondrosarcoma 和 glioblastoma are two examples of cancers harboring these mutations. Interestingly, patients with glioblastoma showing mutant IDH1 have lower levels of expression of the nuclear membrane protein LMNB1 (Lamin-B1) compared to wild type patients who have increased expression, with higher grade tumors showing highest levels. Nuclear lamins play important roles in the anchorage of peripheral elements of chromatin, in regulating the organization of chromosome territories, 在基因表达中. 软骨肉瘤两者都有 IDH1, or IDH2 突变基因，很少两者都有. This allows us to investigate IDH2mut/IDH1wt cells for expression of LMNB1 和 to determine whether different carcinogenic pathways are active in IDH1 vs IDH2 mutant chondrosarcoma cells.
Chondrosarcomas (CS) are the second most common form of bone cancer with high malignant potential 和 resistance to chemo 和 radiation therapies. Treatments have not advanced in the last three decades 和 overall survivability is reduced close to zero in patients with inoperable 和 late-stage CS tumors, highlighting a critical need for treatment options targeting early events. We are investigating critical pathways directly applicable to CS 和 importantly, to other tumors harboring similar defects including, 1); the consequences of acquiring IDH1 or IDH2 mutations, 2); levels of differential LMNB1 表达 IDH1 / IDH2 突变体CS及其影响 LMNB1 核稳定性表达式, 3); mechanisms of nanosecond pulsed electric field exposure on nuclear membrane disruption, 4); changes in gene expression as a result of hierarchical rearrangement of DNA due to differential expression of LMNB1 和 5); therapeutic measures. 而 IDH1 / IDH2 突变和 LMNB1 expression are considered significant events in the carcinogenic process, preclinical/clinical options enabling multi-targeting of the biology associated with these mutations are lacking. Mutant IDH1 和 IDH2 processes occur in the cytosol 和 in the mitochondria, 分别, where the availability of the D2HG generated oncometabolite to other cells is dependent on the mode of transport from one cell to another. D2HG produced in the cytosol by IDH1 is readily available for transfer either as cargo in vesicles or direct secretion into the extracellular milieu, whereas D2HG produced in the mitochondria by IDH2 is available to other cells through mitochondria transfer. D2HG can accumulate in parent 和 recipient cells affecting cellular physiology 和 increasing oncogenicity by: 1) Induction of aerobic glycolysis by preventing the breakdown of hypoxia-inducible factor 1-alpha (HIF1-a), generating a switch from aerobic oxidative metabolism to aerobic-glycolytic metabolism; 2) Induction of DNA hypermethylation resulting in dysregulated gene expression; 和 3) Reduction of immune responses through decreased activation of natural killer T-cells (NK), 辅助t细胞(CD4), 和 differentiation of dendritic cells (DCs).
The over-expression of the nuclear membrane protein lamin-B1 has been shown in other cancers to induce increased proliferation, however its role in the carcinogenic processes in chondrosarcomas are unknown. We have shown in other cancer types that lamin-B1 is expressed 和 that some cancer types show rupture of the nuclear membrane following exposure to nsPEF, 而另一些则没有(图2). We will determine any correlation of LMNB1 expression with sensitivity to nsPEF 和 determine additional epigenetic changes because of nsPEF exposure.
A) Phase contrast image of two chondrocytes joined by a membrane nanotube bridge (white arrow). B) Mitochondria (green) apparently shared between two SW1353 cells (arrowed).
Cells stained for Lamin-B1 showing normal nuclei 和 ruptured nuclei following exposure to nsPEF. 从 史黛丝米, et al (2011) Nanosecond pulsed electric field induced cytoskeleton, nuclear membrane 和 telomere damage adversely impact cell survival. 生物电化学. 82 131-134