BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10515304
• 负责人: YUN-FAI CHRIS LAU
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515304
• 关键词: Acceleration; Affect; Alzheimer' s Disease; Animal Model; Authorization documentation; Award; Bacteria; Binding; Bioinformatics; Biological Markers; Biology; CDC2 gene; California; Cardiovascular Diseases; Cardiovascular system; Cell Proliferation; Cells; Chromosome Mapping; Chromosomes; Chromosomes, Human, Y; Clinical; Clinical Management; Cloning; Cloning Vectors; Code; Collaborations; Cyclin B; DNA Library; Databases; Development; Diagnosis; Disease; Disease Progression; Ectopic Expression; Educational workshop; Elderly man; Embryo; Epithelial Cells; Equipment; Family; Feedback; Foundations; Funding; Gene Activation; Genes; Genetic; Genetic Materials; Genetic Models; Genetic Predisposition to Disease; Genetic Transcription; Genome; Genomic Instability; Genomics; Gonadal structure; Gonadoblastoma; Health; Health Services Research; Healthcare; Healthcare Systems; Hepatocyte; Histones; Homologous Gene; Hormone Receptor; Human; Human Genome; Immunologic Surveillance; Impairment; Incidence; Inhibition of Cell Proliferation; International; Journals; Knowledge; Laboratories; Laboratory Finding; Link; Lysine; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mammalian Cell; Maps; Mediating; Medical; Methods; Molecular; Molecular Genetics; Myocardial Infarction; Nature; Neurodegenerative Disorders; Oncogenes; Oncogenic; Outcome; Pharmaceutical Preparations; Physiology; Pilot Projects; Population; Predisposition; Prognosis; Property; Prostate; Proteins; Proto-Oncogenes; Publishing; Recombinant DNA; Reporting; Research; Research Personnel; Risk; Role; San Francisco; Science; Scientist; Screening procedure; Series; Sex Chromosomes; Sex Differences; Signal Pathway; Somatic Cell; Stem Cell Factor; Stimulation of Cell Proliferation; System; TK Gene; TSPY1 gene; Techniques; Technology; Testing; Testis; Therapeutic; Time; Tissues; Transactivation; Transgenes; Transgenic Mice; Treatment outcome; Tumor Suppressor Proteins; United States National Academy of Sciences; Universities; Validation; Variant; Veterans; Work; X Chromosome; Y Chromosome; authority; biomarker identification; career; chromosome Y loss; design; differential expression; dosage; effective therapy; experimental study; gender disparity; germline stem cells; health care delivery; human disease; human model; improved; insight; interest; lung development; male; male sex hormones; member; mortality; mosaic loss; mouse model; neurogenesis; new technology; next generation sequencing; non-alcoholic fatty liver disease; older men; peripheral blood; postnatal; precision medicine; professor; programs; research and development; sex; sex determination; sexual dimorphism; sry Genes; targeted treatment; therapeutic target; tool; transcription factor; translational applications; translational potential; treatment planning; treatment response; tumorigenesis

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.

Lau博士是Y染色体生物学的国际认可的研究者，并且已建立 人类疾病的分子遗传学和转基因小鼠建模的专家。他已经建立了各种 他的实验室中的分子工具，安装了先进的下一代测序设备和生物信息学 在分子核中，并担任对SFVA此类高级技术感兴趣的PI顾问。 目前，他有几个既定的试点项目。第一个项目的重点是Y位置的角色 肝和前列腺癌中的原始癌基因TSPY。 TSPY是Y的性腺母细胞瘤基因座的基因 染色体（GBY），这是该男性特异性染色体上唯一的致癌基因座。通常，它用作一个 雄性生殖干细胞因子，但作为癌基因，当异位在体细胞中表达时，例如前列腺 上皮细胞和肝细胞。它刺激细胞增殖和细胞周期蛋白B-CDK1激酶活性。 TSPY形式 带有男性性激素受体AR和组成性活性变体AR-V7的正反馈回路，从而 扩大其各自的致癌作用。研究中心探索TSPY之间的相关性， AR/AR-V7表达以及肝脏和前列腺癌的临床特征和结果；和学习 通过实验，TSPY和AR/AR-V7在肝癌和前列腺癌中的肿瘤发生中的贡献。验证 TSPY在AR/AR-V7在肝癌中的雄性占主导地位的作用可能会立即转化 已经开发用于前列腺癌的有效抗AR/AR-V7药物的应用在治疗肝癌中 癌症。第二个项目的重点是TSPY的X位同源物，TSPX对人的肿瘤发生。到期的 为了进化差异，TSPX具有对比特性，即抑制细胞增殖，抑制细胞周期蛋白 B-CDK1和AR/AR-V7反式激活活动，在各种癌症中表现为肿瘤抑制剂， 包括肺，肝脏和前列腺癌。研究旨在识别其各自的致癌性和 肿瘤抑制域和肿瘤发生中的信号通路。第三个项目的重点是 Y染色体（MSY）在各种生理和疾病中的性别差异中的男性特异性区域。 当前的重点是性别确定的基因，这对于确定性别至关重要，但不是 非基达组织的发展。 Lau博士建立了一个有效的转基因激活系统， 证明人类SRY的异常表达在转基因小鼠中诱导各种异常， 包括神经发生和产后肺发育，非酒精性脂肪肝病和 心肌梗塞。正在进行研究以表征疾病的机制，由 在各个组织中的异常表达。第四个项目的重点是最近观察到的链接 在周围血液中Y染色体（MLOY）的镶嵌损失与增加的风险和死亡率之间 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作为癌症以及心血管和神经退行性疾病的筛查工具 退伍军人，例如百万退伍军人计划（MVP）的数据库。他假设MLOY导致 高度保守的X-Y同源基因的剂量不平衡，例如组蛋白赖氨酸脱甲基酶 smcy和uty，导致免疫监测和受影响组织易感性的疾病缺乏 发展。他将使用转基因小鼠模型评估这种遗传易感性，并将其表征 使用先进的基因组学和生物信息学技术，并将结果与​​临床观察结果相关联。 Lau博士是SFVA的关键和贡献者。他建立了一个不断的资助 使用高级分子遗传学，基因组学，生物信息学和转基因小鼠的研究计划 方法。他的研究为精确诊断，预后和目标提供了有用的生物标志物 疗法;以及对性别差异和疾病机制的科学支持，建立至关重要 为我们的退伍军人提供高效提供医疗保健的精确医学。