Role of environmental exposure and inflammation on hematopoietic stem cell disorders

PROJECT SUMMARY/ABSTRACT Environmental exposures, including industrial pollution, automobile exhaust, military burn pits, forest fires, and catastrophic events like the World Trade Center (WTC) collapse, release harmful pollutants such as polycyclic aromatic hydrocarbons (PAHs). These exposures pose significant health risks, including chronic inflammation, cardiovascular disease, lung disease, and an increased susceptibility to hematologic disorders. Our preliminary findings indicate that such exposures increase the incidence of clonal hematopoiesis (CH) and associated hematopoietic defects in exposed individuals, driving inflammation and impairing stem cell function. CH, marked by the expansion of hematopoietic cells with somatic mutations (e.g., DNMT3A, TET2), is linked to cardiovascular disease, bone marrow failure, and reduced survival. This project aims to elucidate how environmental exposures lead to hematopoietic stem cell (HSC) dysfunction and the progression of CH. We hypothesize that environmental pollutants trigger inflammation and DNA damage in HSCs, leading to premature aging and the expansion of mutant clones. Specific Aim 1 will investigate whether environmental exposures accelerate hematopoietic aging, particularly through the activation of inflammatory pathways, by leveraging a unique, well-annotated cohort of human blood samples from individuals with documented genotoxic WTC exposure, alongside genetically engineered murine models of environmental exposure. Specific Aim 2 will assess whether exposure-induced genomic instability drives inflammation, explore the underlying mechanisms, and determine if inhibiting inflammatory regulators can reduce mutation accumulation and rescue HSC defects. This aim will also evaluate the therapeutic potential of targeting inflammatory pathways, using murine models and a clinical-grade inflammasome inhibitor that has demonstrated safety and efficacy in reducing inflammation in a pilot clinical trial with healthy individuals. By integrating human samples and innovative in vivo models, this research will uncover critical insights into the molecular mechanisms linking environmental pollution to hematopoietic aging and CH progression. These findings could lead to novel therapeutic strategies to mitigate exposure-related hematopoietic dysfunction and disease.