Grant: Project Grant

Fibrillin-1 is a protein in the connective tissue of many organs, including blood vessels and bone. Abnormalities in the fibrillin-1 gene cause various disorders which lead to severe and continuously developing clinical complications. Examples of this include various forms of Marfan syndrome, stiff skin syndrome, dominant Weill-Marchesani syndrome, acromicric and geleophysic dysplasias, familial tall stature, ectopia lentis, among others. It is estimated that about 1 in 3,000-5,000 individuals suffer from one of these disorders, resulting in high levels of physical and mental distress for patients and families, in addition to immense costs for the health care system. Marfan syndrome is the most frequent disorder in this group. We have recently found that the molecular interaction of fibrillin-1 with connective tissue cells controls a group of important regulatory molecules, the so-called microRNAs. These are molecules within cells that determine which proteins are produced. We also found that some of these microRNAs are dysregulated in a Marfan syndrome mouse model. The current proposal aims to determine how fibrillin-1 regulates different microRNAs under physiological conditions, and to identify some that can be exploited therapeutically in the long term in Marfan syndrome. We will use cell culture and genetically modified mice affected with Marfan syndrome as model systems. We will identify microRNAs and the genes they control in normal and in the disease situation, and define their function in relation to fibrillin-1. Since microRNAs are very small molecules, they can be potentially used for therapeutic approaches. In this context, we will explore whether inhibition or elevation of some microRNAs in mice leads to an improvement of the typical disease symptoms in blood vessels and bone. The identification of microRNAs in the pathogenesis of Marfan syndrome has the potential to open new avenues for novel treatment strategies for the affected patients.