Research Projects

Rationale in Existing Knowledge: Retinoblastoma (Rb) is the most common childhood malignancy in children. Chemoresistance continues to represent a major challenge leading to treatment failure in retinoblastoma patients to salvage the eyeball. Our previous studies showed the implication of mitochondrial damage in Rb. This suggests that mitochondrial retrograde signaling (mitochondria to nuclear) can lead to changes in nuclear gene expression, which in turn alter metabolic changes in tumor microenvironment of Rb and how the information of mitochondrial DNA (mtDNA)-encoded proteins translocate to nucleus is not clear. Therefore, the purpose of this study is to elucidate the underlying mechanisms of altered mitochondrial function and activation of retrograde signaling pathway in tumorigenesis of Rb. Novelty: This will be the first study to explore mitochondrial retrograde signaling and metabolic profiling in primary and chemoreduced retinoblastoma that helps in understanding the metabolic adaptations and signaling pathways involved in tumor development, progression, and response to chemotherapy. Objectives: The objectives of this study include the characterization of genomic variations in both mitochondrial DNA (mtDNA) and nDNA (aim 1), comparative analysis of differentially expressed mitochondrial-encoded and nuclear-encoded mitochondrial genes and signaling pathway (aim 2), and untargeted/targeted metabolomic profiling (aim 3). Additionally, to characterize mitochondrial biogenesis and mass (aim 4) in primary (group I) and chemoreduced retinoblastoma (group II) patient samples. Methods: The study employs whole exome sequencing, oxford nanopore sequencing, RNA sequencing, pathway enrichment analysis, qRT-PCR, mass spectrophotometry, western blotting techniques, and statistical analysis. Expected Outcome: The completion of this project will identify the pathway that interplay between mitochondrial retrograde signaling, metabolic alterations, and chemotherapy response for identification of biomarkers and potential therapeutic targets to improve outcomes for patients with primary and chemoreduced retinoblastoma.

Pediatrics, retinoblastoma, mitochondrial DNA, retrograde signaling, transcriptomics, mitochondrial biogenesis