Reduction of Carbonyl Stress for the Prevention of Diabetic Kidney Disease
Vivek Bhalla   (New York, NY)
Oxidative stress has long been heralded as an attractive therapeutic option for many diseases including diabetic kidney disease (DKD). Thus, antioxidants have been attempted to treat DKD. However, these strategies to combat oxidative stress involve free radical scavengers which mop up dangerous reactive oxygen species within the cell. These therapies have generally been disappointing for DKD, because the sheer quantity of oxidative stress quelches the ‘antioxidant’ molecules, and does not provide sustained benefit to the patient. A new class of therapeutics developed by the Mochly-Rosen laboratory here at Stanford focuses on activating enzymes present within the body to break down these reactive oxygen species. These types of therapeutics would obviate the need to supply the patient with copious amounts of anti-oxidants because the drug would be stable over time. We have intriguing preliminary data to suggest that one such therapeutic, termed Alda1, can modify a specific enzyme, aldehyde dehydrogenase 2 (ALDH2), within the kidney to prevent the onset of DKD. This work would provide a novel approach to the treatment of this increasingly prevalent disorder. Our specific aims are designed to test the efficacy of Alda1 in diabetic mouse models and to use the drug to directly study the mechanism of oxidative stress-induced damage in cells. These experiments will open the door for further funding to better understand the role of oxidative stress in the kidney and to optimize management of this disorder. The experience of the principal investigator has been in molecular biology and cell signaling, and he will now shift his focus towards understanding and treating DKD. The PI has a previous history of publication in DKD at an earlier stage of training. This prior experience and his clinical background in Nephrology have inspired this new direction for the laboratory to engage this challenging, unmet need in research. The proposed research will be an important step toward developing new therapeutics to prevent DKD, and will be performed in the broader context of a research program dedicated to studying DKD.