It has long been recognized that gene-environment interactions influence the clinical course of individuals with FA, yet the underlying mechanisms remain elusive. Drawing on this labs deep expertise in protein folding diseases this project proposes a pragmatic approach to address this issue which can directly impact FA patients. This work will seek to identify small molecules that can protect FA pathway integrity from environmental perturbations and represent promising leads for slowing disease progression. In addition, this project will identify harmful environmental factors and those FA mutants most susceptible to them, allowing stratification of FA patients based on their susceptibility to environmental stress. Achieving these aims will provide unprecedented insight into the molecular underpinnings that shape the FA phenotype. In turn, such insight will enable the refinement of diagnostic tools to guide more precise, more effective management of each individual patient.