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，也是一位公认的 在人类疾病的分子遗传学和转基因小鼠模型方面的专家。他已经建立了各种 在他的实验室里，安装了先进的下一代测序设备和生物信息学 在分子核心，并在SFVA担任对这种先进技术感兴趣的PI的顾问。 目前，他有几个已建立和试点的项目。第一个项目侧重于Y-Locate的角色 原癌基因TSPY在肝癌和前列腺癌中的研究TSPY是Y染色体上的性母细胞瘤基因 染色体(GBY)，这是该男性特有染色体上唯一的致癌基因。通常，它的功能是作为 雄性生殖细胞干细胞因子，但作为癌基因在体细胞中异位表达，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-CDK1的活性。TSPY表格 与男性性激素受体AR和结构性活性变异体AR-V7形成正反馈环，从而 放大它们各自的致癌作用。研究集中在探索TSPY和TSPY之间的相关性， AR/AR-V7在肝癌和前列腺癌中的表达及临床特征和预后 实验研究TSPY和AR/AR-V7在肝癌和前列腺癌发生中的作用。验证 TSPY在AR/AR-V7中的作用在肝癌中的男性显性可能提供即时翻译 前列腺癌高效抗AR/AR-V7药物在肝脏治疗中的应用 癌症。第二个项目是关于TSPY、TSPX的X位同源基因在人类肿瘤发生中的作用。到期 对于进化分化，TSPX具有截然不同的特性，即抑制细胞增殖，抑制细胞周期 B-CDK1和AR/AR-V7反式激活活性，并在多种癌症中发挥肿瘤抑制作用， 包括肺癌、肝癌和前列腺癌。研究旨在确定它们各自的致癌和 肿瘤抑制域和肿瘤发生中的信号通路。第三个项目关注的是 男性特有的Y染色体区域(MSY)在不同生理和疾病中的性别差异。 目前的重点是性别决定基因SRY，它对性别决定是必不可少的，但对性别决定不是 非性腺组织的发育。刘博士建立了一套高效的转基因激活系统， 证明了人类SRY的异常表达会在转基因小鼠中导致各种异常， 包括神经发生和出生后肺发育迟缓，非酒精性脂肪性肝病和 心肌梗死。目前正在进行研究，以确定疾病的机制，由 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链路 外周血中Y染色体嵌合体丢失(MLOY)与风险和死亡率增加之间的关系 年长的男人。在与SFVA健康研究科学家的合作中，刘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，如组蛋白赖氨酸去甲基酶的剂量失衡 SMCY和UTY，导致免疫监测不足和受影响组织对疾病的易感性 发展。他将使用转基因小鼠模型来评估这种遗传易感性，并对其进行表征 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的重要成员和贡献者。他开发了一种持续资助的 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 接近了。他的研究为肿瘤的精确诊断、预后和靶点提供了有用的生物标志物。 治疗学；以及性别差异和疾病机制的科学支持，这对建立 为退伍军人提供高效、有效的医疗保健的精准医疗。

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.