Understanding the molecular basis of APOL1-mediated kidney disease: a single- cell spatial approach

A single genetic variant in the APOL1 gene can dramatically increase a person’s risk of kidney failure, yet no one knows exactly how it damages kidney tissue at the molecular level. This matters because people of recent African ancestry carry these risk variants at high frequency, and they are disproportionately affected by a severe kidney disease called focal segmental glomerulosclerosis (FSGS). Without treatment, FSGS progresses to kidney failure, requiring dialysis or a transplant. Two different risk variants, G1 and G2, are linked to distinct patterns of kidney dysfunction, but the underlying molecular mechanisms remain unknown—blocking the development of targeted treatments. The researcher will use spatially resolved omics technologies to map gene activity and protein expression in individual cells from human kidney biopsies, comparing samples from patients with different APOL1 genotypes. This will reveal the specific molecular signatures of glomerular damage at single-cell resolution. If successful, this fundamental science project will provide the first detailed molecular map of how APOL1 variants drive kidney injury. That knowledge is a prerequisite for designing better diagnostics and treatments tailored to this underserved population, potentially shifting how kidney pathology is understood and managed.