Neurofibromatosis affects 1 out of 3,500 individuals and results from mutations in the NF1 tumor suppressor gene. Vasculopathies or premature diseases of major blood vessels constitute a major source of complications and death in NF1 patients. Specifically, NF1 patients develop blood vessel diseases including renal artery stenosis and arterial occlusions that result in poor blood flow to major organs including the brain, kidney, and heart. These diseases can lead to premature stroke, hypertension, or even heart attacks. In support of these clinical observations, in 2001, an analysis of 3,253 death certificates of persons with NF1 indicated that the median age of death for NF1 patients was 15 years less than that of the general population. In this report, a diagnosis suggestive of NF1 blood vessel disease was listed 7.2 times more often than expected among NF1 patients less than 30 years old at time of death and 2.2 times more often than expected among patients 30 to 40 years old at the time of death. Based on these studies, vascular disease is now considered the third leading cause of death in NF1 patients. However, despite these observations, the role of neurofibromin in regulating adult endothelial cell and vascular smooth muscle cell function (the two critical cell types necessary for normal blood vessel function) is incompletely understood and is an understudied area in the field of NF1 research.

Studies outlined in this application will directly address this lack of knowledge and are imperative for understanding NF1 vasculopathy and the rational design of drugs for clinical trials to treat NF1 patients with blood vessel diseases. A major obstacle in understanding the causes of NF1 vasculopathy is the lack of an animal model or an experimental system that replicates the human disease. Based on a series of recent experiments performed in our laboratory, we developed a mouse model of NF1 vasculopathy and identified distinct molecular events that may contribute to NF1 vascular disease. Therefore, this application proposes a series of experiments to better understand how loss of neurofibromin in different cell types contained in blood vessels leads to vascular disease utilizing state-of-the-art genetic mouse models. These studies will provide significant insights into how NF1 patients develop premature vascular disease. Further, these preclinical models will also be used to identify potential drug targets in blood vessel wall cells for initiation of Phase I clinical trials in NF1 patients.