Mechanisms of cellular oxidative stress in aldosterone-producing adenomas and adjacent adrenal cortex in primary aldosteronism

• Applicant: Tracy Ann Williams, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 570979695

Primary aldosteronism (PA), the most common cause of secondary hypertension, is frequently driven by somatic mutations in aldosterone-producing adenomas (APAs). Despite affecting 5-10% of hypertensive patients, PA remains vastly underrecognised (<1% diagnosed), contributing significantly to preventable cardiovascular morbidity. Despite our prior evidence establishing oxidative stress and genotype-specific redox adaptations as key contributors to APA pathophysiology, the mechanisms bridging these adaptive responses to tumor survival persist as a critical barrier to therapeutic translation. This DFG proposal addresses this gap by investigating how PA-driver mutations in KCNJ5, CACNA1D, ATP1A1, and ATP2B3 rewire redox homeostasis through chromatin remodelling, conferring cell survival advantages that are mechanistically linked to aldosterone overproduction. The work integrates three hypothesis-driven phases: (1) Multi-omics discovery of mutation-dependent oxidative stress enhancers via single-nucleus RNA/ATAC-seq and spatial transcriptomics; (2) Spatial and functional validation of redox pathways in primary APA cultures using live-cell confocal imaging and pharmacological interventions (RSL3, ML385); and (3) Mechanistic dissection of ferroptosis resistance and cell density-driven adaptation via PiggyBac-engineered cell models- a versatile genome-editing tool enabling titratable, scarless integration- with cumate-inducible promoters and 3D spheroids to mimic dynamic tumor microenvironments. Employing cutting-edge methodologies (eg, PiggyBac-based enhancer-reporter assays, dynamic redox imaging), the project pioneers genotype-specific redox mapping in APA. This approach leverages our lab’s validated expertise in titratable, non-toxic gene manipulation to dissect stress adaptation. Expected outcomes include genotype-specific enhancer networks (e g GPX4 loci) and preclinical evidence for targeting redox homeostasis in APA, directly informing mutation-guided therapies. By advancing genotype-specific therapeutic discovery in PA and equipping early-career researchers with expertise in integrated omics, high-throughput bioinformatics, and titratable gene regulation, this proposal aligns with DFG priorities in methodological innovation, translational bioscience, and sustainable research capacity building.

• DFG Programme: Research Grants