This proposal involves development of a new mouse model and generation of preliminary data that will facilitate transition from the current K award t independence. Acute kidney injury (AKI) is associated with morbidity and mortality in hospitalized patients. Apico-basal polarity is required for directional transport in renal epitheli and is disrupted in AKI. Partitioning defective Par1a and 1b are serine threonine kinases that establish apico-basal polarity in cell culture, but also regulate downstream pathways that affect cell-cell adhesion, cell cycle, cell survival and other pathways that are relevant for epithelial repair. The underlying hypothesis of these studies is that Par1a/b are protective in the setting of acute kidney injury and contribute to renal epithelial repair. To test this, we will generate a mouse model for inducible kidney specific deletion of Par1a/b using CRISPR/Cas9 mediated genome engineering, and examine the effect of loss of Par1a/b on severity of acute kidney injury. In addition, we will examine the relevance of Par1a/b induction after injury, by examining expression of Par1a/b in human kidney tissue (left over, not needed for diagnosis) with pathologic evidence of AKI.
The specific aims are:
Aim1 : Generate a model of inducible kidney specific deletion of Par1a/b.
Aim2 : Determine effect of Par1a/b deletion on severity of acute kidney injury in mice, and Aim3: Examine the expression of Par1a/b in human acute kidney injury.
Acute kidney injury affects 3-7% of hospitalized patients and is associated with increased morbidity, mortality and health care costs. These studies will develop a tool that to examine new signaling pathways that may affect recovery from acute kidney injury. This may improve our understanding of the pathogenesis of acute kidney injury and may lead to new targets for biomarkers and therapeutics.
| Reidy, Kimberly J; Hjorten, Rebecca; Parekh, Rulan S (2018) Genetic risk of APOL1 and kidney disease in children and young adults of African ancestry. Curr Opin Pediatr 30:252-259 |
| Rosenblum, Stacy; Pal, Abhijeet; Reidy, Kimberly (2017) Renal development in the fetus and premature infant. Semin Fetal Neonatal Med 22:58-66 |
