The role of tissue kallikrein 1 in hematopoietic stem cell transplant-associated thrombotic microangiopathy
A deadly complication known as hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) can occur after bone marrow transplant, a curative therapy for malignancy. HSCT-TMA results in injury to small blood vessels throughout the body, preventing red blood cells from delivering oxygen to tissues. This can damage multiple organs, especially the kidneys. The cause of the disorder is unknown and there are limited effective drug therapies, making diagnosis and treatment difficult. Outcomes are dismal, with a high death rate and long-lasting kidney disease in survivors. Consistent with other centers, in our cohort of patients with HSCT-TMA at Texas Children’s Hospital since 2011, 58% died. Of the survivors, 94% developed chronic kidney dysfunction, leading to poor quality of life in childhood cancer survivors. We have previously found that part of the immune system called the complement system is overactive in patients with HSCT-TMA. The normal job of the complement system is to help fight infections such as bacteria when they enter the body. When the complement system is activated, several proteins (called activation products) are cut as a normal part of fighting infection. We believe that HSCT-TMA is caused by overactivity of the complement system and that a specific protein called tissue kallikrein 1 (KLK1) is responsible for creating these activation products, which then damage kidney blood vessels.
Project Goal:
We will perform experiments on kidney blood vessel cells and in mice to help us determine how KLK1 is causing complement activation and kidney injury. We will develop mouse models that cannot make KLK1 or its regulator kallistatin. Using these models, we will try to understand how an imbalance in KLK1 activity may negatively affect the immune system to cause blood vessel damage and kidney injury in HSCT-TMA. Our goal is to establish the cause of HSCT-TMA so that we can help our patients survive with minimal long-term complications after pediatric cancer, improving quality of life and longevity.
