IDO1 and Dysregulated Tryptophan Metabolism in Polycystic Kidney Disease
Abstract
This proposal addresses the Fiscal Year 2022 Peer Reviewed Medical Research Program portfolio category Internal Medicine with the focus on the Topic Area Polycystic Kidney Disease (PKD). PKD is one of the most common genetic disorders. The adult-onset form of PKD, autosomal dominant PKD (ADPKD), affects ~1 in 800 people in the world and is considered the most frequent, life-threatening genetic kidney disease. Given our country’s ~67.5 million military personnel, Veterans, and military family members, an estimated 135,000 have ADPKD, representing ~27% of the total ADPKD population within the United States. ADPKD is characterized by progressive enlargement of the kidney, caused by growth of fluid-filled cysts, leading to crowding of normal kidney tissue and eventual kidney failure, which is the key long-term complication and comorbidity of the disease. In 50% of patients, loss of kidney function requiring dialysis or transplantation occurs by 60 years of age. To date, there is only one approved therapy, tolvaptan, to slow the progression of ADPKD. However, it is only approved for patients with very rapid cyst growth, and it impairs quality of life. Therefore, understanding the processes that drives kidney cyst growth better, to then identify and test new treatment options, is of high priority in PKD research. Critical insight into the mechanisms that drive cyst growth could be gained by understanding why at times cyst grow rapidly and kidney failure happens at a young age or why at times cysts grow slowly and patients don’t face dialysis until old age. In the past few years, research has identified changes in metabolism and immune cell function to be critical modifiers of cysts growth. However, the cellular and molecular mechanisms mediating these effects are not well understood. In our preliminary studies using a mouse model of ADPKD that mimics the disease characteristics found in patients, we identified tryptophan metabolism as one metabolic pathway that is highly dysregulated as disease progresses. Breakdown of tryptophan produces molecules called kynurenines that have been shown to block the immune system and promote cell proliferation. In cancer, a disease that has many pathological parallels with PKD, this pathway is associated with tumor growth, and inhibitors of the pathway have been shown to slow cancer progression and reduce metastases. We found that products of tryptophan breakdown are highly elevated in our model, and we confirmed the importance of the pathway to kidney cyst growth by genetically deleting as well as pharmacologically inhibiting the key enzyme metabolizing tryptophan (IDO1) in two different ADPKD models. These manipulations significantly slowed kidney cyst growth. Our studies also found that the function of different types of immune cells is compromised in the setting of PKD. The immune cells affected are known to be critical players in cancer progression. Interestingly, inhibition of tryptophan metabolism corrected functional immune cell defects in our mice, potentially contributing to the slowed cyst growth. In our proposal, we will utilize a multitude of highly sophisticated tools to understand how dysregulated tryptophan metabolism regulates kidney cyst growth at a single cell level. We will then confirm our findings by manipulating various aspects of the process, e.g., IDO1 expression in different cell types, or functions of various immune cells or kidney epithelial cells, within different ADPKD models. Most importantly, we will test the therapeutic efficacy of an IDO1 inhibitor that is approved in the United States to treat various forms of cancer in our ADPKD models. Therefore, our proposal follows the strategic goal to perform foundational studies that improve the understanding of a long-term complication and comorbidity of PKD – end-stage kidney disease – due to cyst growth. This project is innovative as it focuses on a metabolic pathway that has not been mechanistically or th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310255
Entities
People
- Katharina Hopp
Organizations
- United States Army
- University of Colorado Denver