Modeling Renal Anomalies Associated with Li-Fraumeni Patients: A Novel Role for p53 in Kidney Development

Alejandra Davila-Valadez, BS (Advisor: Rachel Miller, PhD)

          Li-Fraumeni syndrome (LFS) is a heritable disorder caused by germline mutations in the TP53 gene that result in an increased risk of cancer. The TP53 tumor suppressor gene regulates cell division and prevents the accumulation of cells that may become cancerous. LFS patients are susceptible to various types of cancers, including osteosarcoma, soft tissue sarcoma, acute leukemia, and adrenal cortical tumors, as well as breast and brain cancer. Additionally, these patients have an increased risk of developing kidney, stomach, colon, pancreas, esophagus, lung, and gonadal germ cell cancers. Prior studies indicate that p53 is involved in kidney development. However, there is no confirmed link between Li-Fraumeni TP53 patient mutations and kidney abnormalities. Nevertheless, collaborative data indicates these patients have an increased prevalence of urogenital anomalies as compared with the general population. Considering individuals with LFS are predisposed to cancer due to mutations in TP53, and they have a higher occurrence of congenital anomalies of the kidney and urinary tract, our goal is to determine whether germline disruption of p53 contributes to kidney developmental anomalies. Here, we establish a foundation for future analysis of the molecular mechanism(s) by which p53 influences kidney development. Additionally, we show that kidney-targeted p53 manipulation profoundly disrupts the development of multiple nephron segments in Xenopus embryos. Future studies will further explore the role of p53 in nephron development by modeling the effects of Li-Fraumeni patient-derived mutations in the developing kidney.

Advisory Committee:

• Rachel Miller, PhD, Chair
• Mir Reza Bekheirnia, MD
• Francesca Cole, PhD
• Yoshihiro Komatsu, PhD
• Amy Sater, PhD