Summary
Research to elucidate how Parkin, a mitochondria-associated E3 ubiquitin ligase, functions as a dual-mode tumor suppressor by inhibiting tumor traits and reprogramming an antitumor immune microenvironment, focusing on its role in innate immunity and interferon signaling.
What they want
The project will investigate the role of Parkin innate immunity in tumor suppression through three specific aims. The first aim will characterize how Parkin 'primes' immunogenic cell death, elucidate the role of ER stress and autophagy in mitochondrial necroptosis, and map the cellular and biochemical requirements of Damage-Associated Molecular Pattern (DAMP) release. The second aim will dissect the signaling requirements of Parkin activation of innate immunity with respect to cytosolic cGAS-STING and inflammasome activation, mitochondrial RIG-I-MAVS sensing, and assembly of a STAT1-regulated ISGF3 transcriptional complex for T cell activation and dendritic cell function. The third aim will test the impact of Parkin innate immunity in preclinical orthotopic and transgenic models of primary and metastatic tumor growth, in vivo modulation of antitumor vaccination strategies, and differential sensitivity to conventional and immune therapies.
Deliverables
- Characterization of Parkin's role in priming immunogenic cell death
- Elucidation of ER stress and autophagy in mitochondrial necroptosis
- Mapping of cellular and biochemical requirements for DAMP release
- Dissection of signaling requirements for Parkin activation of innate immunity (cGAS-STING, inflammasome, RIG-I-MAVS, ISGF3 complex)
- Evaluation of Parkin innate immunity impact in preclinical tumor models
- Assessment of Parkin's modulation of antitumor vaccination strategies
- Analysis of differential sensitivity to conventional and immune therapies based on Parkin innate immunity
