Instructor in Medicine
Washington University School of Medicine
Mysorekar, Indira, Ph.D., Minor, Jeff, Ph.D., and Chen, Feng, Ph.D.
Conxing Lin, Ph.D. graduated from Beijing University in China in 2001, where he majored in cell biology and genetics. Dr. Lin came to the United States and started his Ph.D. studies in the Human Genetics Program at Tulane University School of Medicine. In 2004, he moved to St. Louis, and joined the laboratory of Dr. Liang Ma in Washington University to continue his dissertation research on the female reproductive system. In 2008, he received his Ph.D. degree from Tulane University and became a joint postdoc with Dr. Indira Mysorekar in the Department of OB/GYN at Washington University, and Dr. Liang Ma. During his postdoctoral training, he studied the biology of the genitourinary tract, and made several seminal contributions to the field of external genital development. Dr. Lin was selected to be one of the recipients of the prestigious American Urological Association (AUA) research scholar award. Since he was promoted to a junior faculty position, he has continued to work with Dr. Mysorekar to develop his own research program on sex-specific mechanisms in bladder diseases.
Dr. Lin’s research focuses on the sex difference in outcomes regarding bladder disease. Men tend to get bladder cancer whereas women are prone to interstitial cystitis. Dr. Lin proposes the hypothesis that developmental signaling through the Wnt pathway differs in men and women and predisposes to different pathophysiology. He has been very productive in his graduate and postdoctoral training. He has published sixteen papers (seven first-authored) in respected journals such as Development, Cancer Research, PLoS Genetics, and Molecular Endocrinology.
Awards and Honors
Dr. Lin was selected to be one of the six recipients of the prestigious American Urological Association research scholar award.
WNT in Urothelial Regeneration and Sex-Specific Bladder Pathogenesis
It was estimated that more than 3.3 million American women have symptoms that may be associated with interstitial cystitis/painful bladder syndrome (IC/PBS). Most epidemiology studies indicate a clear female-predilection for this condition. However, the underlying reason for this gender variation is still unclear. The disruption of urothelial homeostasis is central to the pathophysiology of IC/PBS. The urothelium is normally slow-cycling but also equipped with a remarkable regenerative capacity. Upon damage, the urothelial cells can rapidly proliferate to reconstitute the urothelium and restore its barrier function. This regenerative response is tightly controlled by transcription factors and growth factor signaling. In contrast, the urothelium in IC/PBS pa- tients is unable to self-repair, indicating a deficiency in their regenerative machinery.
WNT is a family of secreted glycoproteins that can initiate a variety of downstream signaling events depending on the cellular context. Previous studies demonstrated dynamic expression of WNT ligands upon urothelial injury. However, the functional relevance of these signaling activities in urothelial regeneration remains unknown. To address this question, we generated a series of mouse models with urothelium-specific gain- or loss-of-function mutations in WNT pathway components. Preliminary characterization of these models revealed opposite roles of two distinct WNT signaling pathways in the urothelium. The canonical WNT/β-catenin pathway induces urothelial cell proliferation and promotes differentiation, while the non-canonical WNT/calcium pathway maintains progenitor cells and suppresses differentiation. Intriguingly, we also found that the male urothelium is more responsive to WNT/β-catenin signaling than the female urothelium. Based on these observations, we hypothesize that 1) the activation of the WNT/β-catenin pathway is essential for promoting urothelial prolifer- ation and differentiation in urothelial regeneration (Aim1), 2) the intrinsic sex difference in canonical WNT respon- siveness contributes to differential regenerative capacity in males and females (Aim2), and 3) WNT/β-catenin signaling is normally antagonized by WNT5a signaling, whose inhibition is released upon injury (Aim3). These hypotheses will be tested using a combination of mouse genetic models and a well-established uropathogenic Escherichia coli (UPEC)-induced bladder injury model. This study will establish a paradigm for WNT activity and define the mechanisms underlying sex differences in urothelial regeneration. This will be an important step to- wards our long term goals to understand the implication of intrinsic sexual dimorphism in bladder diseases, and develop targeted therapies for urothelial deficiencies.