Year 3

Kidney function is essential for removing the wastes that result from normal cell function and maintaining water and salt balance in our internal tissues. These actions are carried out by roughly a million nephrons within the kidney that filter all the body’s blood roughly once every 1-2 hours. The kidney also regulates other
tissues controlling blood pressure and blood cell composition, and regulating the strength of bone by activating vitamin D. C hronic kidney injury over time results in a loss of normal kidney function leading to end stage renal disease (ESRD). ESRD affects 500,000 Americans and its prevalence is increasing with a rise in diabetesand hypertension. ESRD is associated with significant morbidity and mortality: ultimately kidney transplant is the only cure but for every four patients requiring a transplant there are only enough available kidneys to help one. Life-threatening kidney injury also occurs through acute damage particularly in hospital settings were infection, toxic drugs or ischemia during surgery kills cells in the nephron shutting down the kidneys. Animal studies indicate that the kidney is unable to make new nephrons: the full complement of nephrons for life are established prior to birth. However, the damaged nephron has a limited capacity to restore activity through the regeneration of missing cells by their surviving neighbors.
Our research has focused on an understanding of the damage/repair process following acute kidney injury to identify new therapeutic opportunities. We have utilized a mouse model to generate a BioBank resource of injured and repairing kidney samples. Further, we have generated a novel approach that allows the investigator to focus on injury and repair responses within specific cellular compartments in the kidney. As an example, this approach allows us to investigate changes in gene activity within the nephron itself, or in the blood vessels that engulf the nephrons. Both are targets of injury and effective repair will likely involve solutions for each of these components of the kidney. We have generated a large informational base andstarted to mine this data to identify genes with the potential to direct or augment renal repair. Using modern genetic strategies we are now exploring the roles of several of these genes. Our goal is to move from discovery to translation of those discoveries during the course of this C IRM leadership award.