Project 461447

Fibrillin-1 is a protein located outside of cells where it forms large fibers termed microfibrils. Genetic mutations in the fibrillin-1 gene cause Marfan syndrome (MFS) and related disorders. Patients affected with MFS have problems in fat tissue formation and function. Some patients have very little fat and others, especially older patients, develop more than normal fat tissue. This correlates well with two mouse models with reduced or deleted fibrillin-1 at different stages of fat cell development. When fibrillin-1 is deficient early in the formation of fat cells in one of the mouse models, more fat tissue develops and when it is deleted late in another mouse model, less fat tissue develops. Therefore, it is clear that fibrillin-1 plays an essential and dual role in fat cell and tissue development, function, and metabolism. How fibrillin-1 deficiency derails fat tissue development and metabolism in physiological or pathological conditions is not understood. This study addresses this question by using mouse and cell culture models, in combination with recombinantly produced fibrillin-1. The mouse models will provide a system where fibrillin-1 is deficient either early or late in fat cell development. We will investigate the fat tissue of these mice by various molecular biology techniques to understand the consequences of reduced or deleted fibrillin-1 at different stages on the respective cells and their microenvironment. With stem cells isolated from either bone marrow or fat tissue of these mice, we will study molecular pathways. We will also investigate how fibrillin-1 mutations affect fat cell development in cell culture models. The available data so far predict that fibrillin-1 has dual roles in the development and maintenance of fat cells and tissue, and this project will identify novel mechanisms in this context. We expect unique information that can be used later to develop therapeutic approaches in MFS and related disorders.