Unraveling the Role of p53 in Endothelium Homeostasis after Ionizing Radiation Exposure

Project summary Radiation therapy is an important component of cancer treatments, yet its usage has been hampered due to side effects to normal tissue. The current K99/R00 project seeks to investigate the molecular landscape of radiation induced coronary heart disease (RICHD), a leading cause of morbidity and mortality among cancer survivors. The complex nature of RICHD necessitates a comprehensive understanding of patient-specific risk factors and underlying genetic variations. Focusing on the pivotal role of endothelial to mesenchymal transition (EndMT) and its correlation with variations in p53 signaling due to TP53 mutations, I will utilize human-induced pluripotent stem cells (iPSCs) from cancer patients with TP53 mutations and transgenic mouse models in the mentored K99 phase. In my first aim, I will utilize 3D vessel-on-a-chip model (VoC) lined with iPSC-derived endothelial cells and smooth muscle cells from cancer patients with or without TP53 mutations for longitudinal endothelial lineage tracing analysis with vascular functional assays after exposure to 2 Gy of X-rays radiation. In my second aim, I will generate a novel endothelial lineage tracing mouse model with TP53 mutations and elucidate the functional and molecular alterations after exposure to 20 Gy of X-rays radiation on the heart. Both projects employ in-depth single cell RNA-sequencing (scRNA-seq) analysis to map the gene regulatory networks perturbations across different cell-types at varied time points post-irradiation. This project will be guided by an advisory committee constituted of researchers bringing their distinct expertise: Joseph Wu (Precision Medicine), Laura Attardi (TP53 Biology), Sharon Gerecht (Vascular Engineering), Billy Loo (Radiation Oncology), Kristy Red-Horse (Lineage Tracing), Michael Snyder (Integrative Omics Analysis). The training received under this mentorship will equip me with invaluable expertise in tissue engineering, lineage tracing and scRNA-seq analysis. Ultimately, this will foster my transition to the independent phase (R00), where I aim to establish genotype-phenotype correlations for RICHD in iPSC-derivatives. Functional radiogenomics on vascular cells will provide novel insights and a roadmap for stratifying TP53 mutations in RICHD offering a significant advancement for cancer patients undergoing radiation therapy.