Despite recent progress, pulmonary arterial hypertension (PAH) remains a lethal disease. Accurate diagnoses of PAH are often severely delayed due to missed or late detection of symptoms, which contributes to a devastatingly low survival rate even with the best treatments. The genes responsible for >80% of idiopathic PAH and >20% of familial PAH have not been identified. The long-term goal of this project is to identify new genes and novel molecular signaling mechanisms for the pathogenesis of PAH, which can lead to the development of innovative strategies for early and accurate diagnosis of PAH before symptoms occur and the discovery of new therapeutic agents and drugs that specifically target the responsible genes and signaling pathways for the treatment of PAH. The AGGF1 gene was initially cloned by the PI's laboratory and shown to encode a novel angiogenic factor that controls the development of blood vessels and regulates the integrity of the vasculature. Recently, we found that AGGF1 is highly expressed in the pulmonary vasculature, but interestingly, its expression is significantly decreased in human PAH patients. A pilot genetic study identified a significant association between genomic at the AGGF1 locus and risk of PAH; heterozygous Aggf1 knockout (KO) mice develop spontaneous PAH. Functional studies showed that AGGF1 regulates intracellular calcium concentrations, expression of p53, and proliferation of pulmonary artery vascular smooth muscle cells. Based on these exciting data, we hypothesize that AGGF1 is a new gene and molecular determinant for the pathogenesis of PAH and that Aggf1 KO causes PAH by regulating the intracellular calcium signaling pathway and the p53 signaling pathway. We propose a systematic approach with integrated molecular and cellular analyses, animal modeling, and human studies to test the central hypothesis. Specifically, we will focus on four areas of research.
We aim to: (1) Establish the critical role of AGGF1 in the pathogenesis of PAH in humans; (2) Establish the critical role of Aggf1 in the pathogenesis of PAH in mice using conditional mouse KO technology; (3) Identify the molecular mechanisms and signaling pathways by which AGGF1 regulates the development of PAH; (4) Target AGGF1 for therapy of PAH. The successful completion of this project will identify a new gene (AGGF1), novel molecular mechanisms, and new signaling pathways for the pathogenesis of PAH, which can serve as new targets for innovative treatments and new drug development. Finally, we will test the potential of the AGGF1 protein therapy as a novel therapy for treatment of PAH, which may lead to a new treatment strategy for human PAH patients. two variants
Despite recent advances, patients who have undergone existing therapies for pulmonary arterial hypertension (PAH) have experienced only modest clinical improvements, and PAH remains a fatal disease. Successful completion of the proposed studies will identify a novel gene and molecular determinant (AGGF1) and a new signaling pathway for the development of PAH, which may lead to development of an early and accurate diagnosis of PAH. This project will also lead to the development of an innovative treatment for PAH based on AGGF1, a novel therapeutic target of PAH.
