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.

刘博士是国际公认的Y染色体生物学研究者，并建立了