BLRD Research Career Scientist Award Application

Veterans Affairs Med Ctr San Francisco, San Francisco CA

Investigators

Linked publications & trials

Abstract

Dr. Lau is an established expert in molecular genetics and transgenic mouse modeling of human diseases and an internationally recognized investigator in the Y chromosome biology. He has a long history of contributions to advances in the fields. He had generated a series of versatile cosmid vectors capable shuttling between bacterial and mammalian cells, and constructed comprehensive human genome recombinant DNA libraries that were distributed and used successfully in many laboratories worldwide in the 80s. He served as the US Chair/Organizer in the International Workshops on the Y chromosome, responsible for establishing the genetic and physical maps of the human Y chromosome in the 90s, forming parts of the foundation for the complete sequencing of this chromosome in the Human Genome Project in 2000s. He had organized numerous elite conferences, such as the Gordon Conferences, in his fields. He has installed advanced next generation sequencing technologies and bioinformatics in the Molecular Core at the SFVA in the 2010s. He is presently the Editor-in-Chief of a biomedical journal, Cell & Bioscience with impact factors of 7.5-9.6 in recent years. His current research focuses on understanding the contributions of the Y chromosome genes, particularly the sex- determining gene SRY and the putative proto-oncogene TSPY, in various sexually dimorphic diseases and cancers using transgenic mouse modeling, molecular genetics and genomics strategies. Dr. Lau demonstrated that SRY could competitively disrupt the gene regulation programs of related SRY-box (SOX) transcription factors, thereby exerting male-specific influences in the affected tissues. He hypothesizes that at low levels SRY could be responsible for various sex differences in the development and physiology normally observed between the sexes. At high levels SRY could promote pathogenesis in sexually dimorphic diseases, such as Alzheimer's disease. Using molecular genetics and transgenic modeling, Dr. Lau has provided evidence supporting his hypothesis. TSPY was initially cloned in Dr. Lau’s laboratory. He showed that it is the gene for the gonadoblastoma locus on the Y chromosome (GBY), predisposing the germ cells of XY females to gonadoblastoma and other germ cell tumors. Importantly, TSPY binds to cyclin B-CDK1 and stimulates its kinase activities, promotes G2/M transition and cell proliferation. TSPY interacts with and exacerbates the transactivation activities of androgen receptor (AR) and constitutively active AR variants. TSPY is also a target of AR/AR variants, thereby forming a positive feedback loop in synergistic amplifications of respective functions between a Y- chromosome gene and male sex hormone receptors. Recently he showed that TSPY is a cancer/testis antigen (CTA), normally expressed in germ cells of the testis, an immune privileged organ, and various cancers, such as hepatocellular carcinoma (HCC), lung, bladder, colon and kidney cancers, under oncogenic conditions. Because of their cancer-specific expression, many CTAs are proposed to be targets for immunotherapy. The suitability of any CTA depends on its cell surface location, ability to elicit immune surveillance and elimination of tumor cells. Since TSPY positivity is the highest in HCC, Dr. Lau has directed his research on this cancer, using an oncogene-induced HCC mouse model. He showed that co-expression of TSPY resulted in significantly smaller tumor in the mice. Subsequent studies demonstrated that TSPY was highly immunogenic, present on the cell surface and elicited robust immune responses and elimination of the positive tumor cells from the host animals. Importantly, immunization of a TSPY-based vaccine to positive mice further inhibited tumor growth and prolonged the lives of these animals. Since liver cancer is 5 times higher among the Veterans than the American public, these new findings are important and provide scientific supports for TSPY as a target for immunotherapy in treatments of positive liver cancer. Thus, Dr. Lau is a key and contributing member of the SFVA. For the next funding period, he will focus on identifying the mechanisms and developing translational applications of TSPY in immunotherapy of liver cancer in both preclinical and clinical settings to improve the Health Care of the Veterans.