BLR&D Research Career Scientist Award Application

刘博士是国际公认的Y染色体生物学研究者， 分子遗传学和人类疾病转基因小鼠模型专家。他建立了各种 在他的实验室中安装了先进的下一代测序设备和生物信息学 在分子核心，并担任顾问的PI感兴趣的这种先进的技术在SFVA。 目前，他有几个既定的和试点项目。第一个项目的重点是Y-定位的作用 肝癌和前列腺癌中的原癌基因TSPY。TSPY是Y染色体上性腺母细胞瘤基因座的基因， 染色体（GBY），唯一的致癌基因位点上的这一男性特异性染色体。通常情况下，它的功能是 男性生殖干细胞因子，但作为一种癌基因异位表达在体细胞，如前列腺， 上皮细胞和肝细胞。它刺激细胞增殖和细胞周期蛋白B-CDK 1激酶活性。TSPY表格 具有雄性激素受体AR和组成型活性变体AR-V7的正反馈环，从而 放大它们各自的致癌作用。研究集中在探索TSPY， AR/AR-V7表达与肝癌和前列腺癌的临床特征和结局; 在实验上，TSPY和AR/AR-V7在肝癌和前列腺癌的肿瘤发生中的作用。验证 TSPY在AR/AR-V7中的作用在肝癌的男性优势中可以提供直接的翻译， 已经开发的用于前列腺癌的有效抗AR/AR-V7药物在治疗肝脏肿瘤中的应用 癌第二个项目是研究TSPY的X定位同源物TSPX与人类肿瘤发生的关系。由于 TSPX具有相反的特性，即延缓细胞增殖，抑制细胞周期蛋白， B-CDK 1和AR/AR-V7反式激活活性，并在各种癌症中作为肿瘤抑制因子， 包括肺癌、肝癌和前列腺癌。研究的目的是确定其各自的致癌和 肿瘤抑制结构域和肿瘤发生中的信号通路。第三个项目的重点是基因上 Y染色体的男性特异性区域（MSY）在各种生理和疾病中存在性别差异。 目前的重点是性别决定基因SRY，它对性别决定至关重要，但对 非性腺组织的发育。刘博士建立了一个有效的转基因激活系统， 证明了人SRY的异常表达在转基因小鼠中诱导各种异常， 包括神经发生和出生后肺发育迟缓，非酒精性脂肪肝， 心肌梗死目前正在进行研究，以确定疾病的机制， SRY在相应组织中的异常表达。第四个项目的重点是最近观察到的联系 外周血中Y染色体嵌合丢失（mLOY）与糖尿病患者的风险和死亡率增加之间的关系 老年人在与SFVA的健康研究科学家的合作中，Lau博士计划探索这种可能性。 使用mLOY作为癌症、心血管和神经退行性疾病的筛查工具， 退伍军人，如百万退伍军人计划（MVP）的数据库。他假设mLOY会导致 高度保守的X-Y同源基因的剂量失衡，如组蛋白赖氨酸脱甲基酶 SMCY和UTY，导致免疫监视不足和受影响组织易患病 发展他将使用转基因小鼠模型来评估这种遗传易感性， 利用先进的基因组学和生物信息学技术，并将结果与临床观察相关联。 刘博士是SFVA的关键和贡献成员。他建立了一个持续资助的 利用先进的分子遗传学、基因组学、生物信息学和转基因小鼠的研究计划 接近。他的研究为精确诊断，预后和靶点提供了有用的生物标志物。 治疗学;以及对性别差异和疾病机制的科学支持，在建立 精准医疗为我们的退伍军人提供高效和有效的医疗服务。

Dr. Lau is an internationally recognized investigator in the Y chromosome biology and an established expert in molecular genetics and transgenic mouse modeling of human diseases. He has established various molecular tools in his laboratory, installed advanced next generation sequencing equipment and bioinformatics in the Molecular Core, and served as consultant for PIs interested in such advanced technologies at the SFVA. Currently, he has several established and pilot projects. First project focuses on the roles of the Y-located proto-oncogene TSPY in liver and prostate cancers. TSPY is the gene for the gonadoblastoma locus on the Y chromosome (GBY), the only oncogenic locus on this male-specific chromosome. Normally, it functions as a male germ stem cell factor, but as an oncogene when ectopically expressed in somatic cells, such as prostate epithelial cells and hepatocytes. It stimulates cell proliferation and cyclin B-CDK1 kinase activities. TSPY forms a positive feedback loop with male sex hormone receptor AR and constitutively active variant AR-V7, thereby amplifying their respective oncogenic actions. Research centers on exploring the correlation between TSPY, AR/AR-V7 expression and clinical features and outcomes in liver and prostate cancers; and on studying experimentally the contributions of TSPY and AR/AR-V7 in oncogenesis in liver and prostate cancer. Validation of the roles of TSPY in AR/AR-V7 in the male-dominance in liver cancer could offer immediate translational applications of effective anti-AR/AR-V7 drugs already developed for prostate cancer to the treatment of liver cancer. The second project focuses on the X-located homologue of TSPY, TSPX on human oncogenesis. Due to evolutionary divergence, TSPX possesses contrasting properties, i.e. retards cell proliferation, inhibits cyclin B-CDK1 and AR/AR-V7 transactivation activities, and behaves as a tumor suppressor in various cancers, including lung, liver and prostate cancers. Studies are designed to identify their respective oncogenic and tumor suppressor domains, and signaling pathways in oncogenesis. The third project focuses on the genes on the male-specific region of the Y chromosome (MSY) in sex differences in various physiology and diseases. The current emphasis is on the sex-determining gene SRY, which is essential for sex determination, but not for the development of non-gonadal tissues. Dr. Lau has established an efficient transgene activation system and demonstrated that aberrant expression of a human SRY induces various abnormalities in transgenic mice, including retardation in neurogenesis and postnatal lung development, nonalcoholic fatty liver disease and myocardial infarction. Studies are being conducted to characterize the mechanisms of diseases, mediated by aberrant SRY expression in the respective tissues. The fourth project focuses on the recently observed link between mosaic loss of the Y chromosome (mLOY) in the peripheral blood and increased risks and mortality in elderly men. In collaborations with Health Research scientists at SFVA, Dr. Lau plans to explore the possibility of using mLOY as screening tool for cancers and cardiovascular and neurodegenerative diseases among the Veterans, such as the databases of the Million Veteran Program (MVP). He hypothesizes that mLOY results in dosage unbalance of the highly conserved X-Y homologous genes, such as the histone lysine demethylases SMCY and UTY, resulting in deficiency in immunosurveillance and predisposition of affected tissues to disease development. He will use transgenic mouse models to evaluate such genetic predisposition, characterize them with advanced genomics and bioinformatics techniques and correlate the results with clinical observations. Dr. Lau is a key and contributing member of the SFVA. He has developed a continuously funded research program using advanced molecular genetics, genomics, bioinformatics and transgenic mouse approaches. His research has provided useful biomarkers for precise diagnosis, prognosis, and targets for therapeutics; and the scientific supports for sex differences and disease mechanisms, essential in establishing the precision medicine for the efficient and effective deliveries of healthcare for our Veterans.