The overall goal of the Program Project is to contribute new knowledge that will lead to the development of future therapies for the Marfan syndrome. Proposed investigations will result in a better understanding of the roles of growth factor signaling in MFS and new knowledge that will impact cellular and temporal targeting of future therapies. Project 3 will use Fbn1 mutant mouse models of aortic disease in order to investigate three specific aims.
In Aim 1, we will test whether inappropriate sequestration of the large latent TGF beta complex is the major mechanism responsible for the initiation and progression of aortic disease in the Marfan syndrome. In order to test this mechanism of disease, we have generated a new mouse model in which the site in fibrillin-1 that mediates binding to the latent TGF beta binding proteins -1 and -4 has been deleted.
In Aim 2, we will test whether the major mechanisms of aortic disease take place in the smooth muscle media of the aorta and whether postnatal synthesis of mutant fibrillin-1 is sufficient to cause aortic disease. To investigate these hypotheses, we have generated a new "conditional" truncating mutation in fibrillin-1 in mice. Proposed investigations will lead to new information on key cellular processes involved in aortic VSMC responses to mutant fibrillin-1. Little is known about the in vivo local effects of ECM on specific cellular compartments of an organ and whether and how the local ECM environment contributes to cellular signaling between compartments in an organ. Studies proposed in Aim 2 will dissect the effects of the local mutant ECM environment on VSMC behavior in aortic pathophysiology. The role of fibrillin-1 during aortic homeostasis, while clearly important, is not well understood. One possibility is that fibrillin-1, produced during development, is required during homeostasis. Another possibility is that fibrillin-1 synthesis is required during homeostasis. Studies in Aim 2 will determine whether and to what extent postnatal expression of mutant fibrillin-1 contributes to aortic disease. These studies will better define the window of opportunity for effective therapeutic protocols.
In Aim 3, we will test whether BMP signaling is abnormally activated in mouse models of aortic disease, when this activation occurs, and whether blocking abnormal BMP signaling will prevent aortic disease in mouse models. Proposed investigations of these mechanisms will include morphological and ultrastructural examinations of the aortic root, quantitative RT-PCR, immunochemical studies, cell culture studies, and in vivo therapeutic trials

Public Health Relevance

These investigations will identify novel mechanisms and pathways involved in aortic disease, will test candidate molecules that may perform significant roles in aortic disease, will specify the contribution of smooth muscle cells to aortic disease, and will determine whether or not aortic disease in MFS is initiated postnatally. These studies will suggest new targets for future therapies and will also contribute to strategies for targeting cellular compartments in the aorta or for optimal timing of future therapies for MFS.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Program Projects (P01)
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Special Emphasis Panel (ZAR1-MLB-F)
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Icahn School of Medicine at Mount Sinai
New York
United States
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Cook, Jason R; Ramirez, Francesco (2014) Clinical, diagnostic, and therapeutic aspects of the Marfan syndrome. Adv Exp Med Biol 802:77-94
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