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Principal Investigator: Won Suk Jahng
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $149,948
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <3-D><3-Dimensional><3D><7B4><Adhesions><Advanced Cancer><Advanced Malignant Neoplasm><Advisory Committees><Animals><Antioncogene Protein p53><Apical><Assay><Autoregulation><Bioassay><Biological Assay><Biology><Blood Vessels><Blood monocyte><Body Tissues><CDH5><CDH5 gene><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cancer Patient><Cancer Survivor><Cancer Treatment><Cancers><Cas nuclease technology><Cell Body><Cell Communication and Signaling><Cell Death><Cell Isolation><Cell Line><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cell to Cell Communication and Signaling><Cell-Cell Signaling><CellLine><Cells><Cellular Tumor Antigen P53><Chromosome Mapping><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Collection><Complex><Coronary Disease><Coronary heart disease><Data><Data Set><Dependence><Diagnosis><Differential Gene Expression><Domestic Horse><Dose><Echocardiogram><Echocardiography><Endothelial Cells><Endothelium><Engineering><Equine><Equine Species><Equus caballus><Equus przewalskii><Event><Exposure to><Expression Signature><Female><Fostering><Gene Expression Profile><Gene Localization><Gene Mapping><Gene Mapping Genetics><Gene variant><Genes><Genetic Alteration><Genetic Change><Genetic Diversity><Genetic Population Study><Genetic Risk><Genetic Variation><Genetic defect><Genotype><Goals><Health><Heart><Heterozygote><Histology><Homeostasis><Horses><Human><Inflammation><Intracellular Communication and Signaling><Investigators><Ionizing Electromagnetic Radiation><Ionizing radiation><Knock-in><Leiomyocyte><Link><Linkage Mapping><Lysosomes><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Maps><Marrow monocyte><Membrane><Mentors><Mentorship><Mesenchymal><Mice><Mice Mammals><Micro RNA><MicroRNAs><Modeling><Modern Man><Molecular><Molecular Fingerprinting><Molecular Profiling><Morbidity><Morbidity - disease rate><Murine><Mus><Mutant Strains Mice><Mutation><Nature><Normal Tissue><Normal tissue morphology><Oncology><Oncology Cancer><Oncoprotein p53><P53><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Permeability><Phase><Phenotype><Phosphoprotein P53><Phosphoprotein pp53><Physiological Homeostasis><Porosity><Protein TP53><Radiation><Radiation Oncology><Radiation exposure><Radiation therapy><Radiation-Ionizing Total><Radiogenomics><Radiotherapeutics><Radiotherapy><Reporter><Research Personnel><Researchers><Risk Factors><Risk-associated variant><Roentgen Rays><Role><Sampling><Sex Distribution><Signal Transduction><Signal Transduction Systems><Signaling><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><Sorting><Strains Cell Lines><Stratification><Syndrome><System><TP53><TP53 gene><TRP53><Task Forces><Technology><Time><Tissue Engineering><Tissue-Specific Differential Gene Expression><Tissue-Specific Gene Expression><Tissues><Total Human and Non-Human Gene Mapping><Training><Transactivation><Transgenic Mice><Transthoracic Echocardiography><Tumor Protein p53><Tumor Protein p53 Gene><Variant><Variation><X-Radiation><X-Ray Radiation><X-ray><Xray><Xray irradiation><advisory team><allele variant><allelic variant><anti-cancer therapy><atherosclerotic heart disease><bioengineered tissue><biological signal transduction><cancer therapy><cancer-directed therapy><career><cell sorting><cell type><cohort><coronary disorder><cultured cell line><design><designing><disease prognosis><disease prognostication><disparities in sex><engineered tissue><entire genome><experimental group><full genome><gene expression pattern><gene expression signature><gene regulatory network><genetic mapping><genetic variant><genome editing><genome mutation><genome sequencing><genomic editing><genomic variant><heart sonography><heterozygosity><hiPSC><human disease><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><iPS><iPSC><iPSCs><improved><induced human pluripotent stem cells><induced pluripotent cell><induced pluripotent stem cell><induced pluripotent stem cells derived from patients><induced pluripotent stem cells from patients><inducible pluripotent stem cell><insight><intercellular communication><ionizing output><irradiation><knockin><malignancy><membrane structure><miRNA><miRNAs><miniaturize><miniaturized><molecular profile><molecular signature><monocyte><mortality><mouse model><mouse mutant><murine model><necrocytosis><neoplasm/cancer><novel><p53 Antigen><p53 Genes><p53 Signaling Pathway><p53 Tumor Suppressor><patient derived human iPS><patient derived human iPSC><patient derived human induced pluripotent stem cell><patient derived iPS><patient derived iPSC><patient derived induced pluripotent cells><patient derived induced pluripotent stem cells><patient oriented outcomes><patient-derived pluripotent stem cells><precision medicine><precision-based medicine><protein p53><radiation risk><radiation treatment><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><scRNA-seq><sex disparity><side effect><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><three dimensional><trans-activation><transcriptional profile><transcriptional signature><transcriptomics><treatment with radiation><vascular><whole genome><x-ray irradiation>