Marfan syndrome (MFS) is a common connective tissue disorder, caused by fibrillin-1 mutations, that is associated with severe skeletal, ocular, and cardiovascular complications including death due to ruptured aortic aneurysms. Our prior work has shown that many manifestations of MFS are caused byexcessive activation of and signaling by TGFbeta, a family of growth factors that regulate cell performance and survival. Loeys-Dietz syndrome (LDS) is a newly recognized and apparently common disorder caused by mutations in either of the two genes that encode the TGFbeta receptor (TBR). MFS and LDS are intimately related conditions, both in terms of clinical manifestations and pathogenetic mechanisms. We believe that the integrated study of both disorders will be particularly powerful. Our foundations derived from prior study of mouse models of MFS will provide a meaningful context within which to interpret newly created animal models of LDS. This will include a dedicated assessment of the lung, bone, skeletal muscle, aorta, and valve leaflets in TBR-deficient animals, both with and without treatment with TGFbeta neutralizing antibody. In contrast to MFS (where signaling defects are initiated by matrix perturbations), the cell-autonomous nature of the defect in LDS will allow rapid and definitive evaluation of other potentially relevant pathogenetic events (including altered angiotensin II (Angll), p38, ERK1/2 and JNK signaling) using cell culture systems and pathway-specific pharmacologic antagonists;positive results will allow for hypothesis-driven interrogation of tissues derived from Marfan mice and patients. We will evaluate for genetic interactions in TBR mutant animals that are also deficient for fibrillin-1 or that conditionally overexpress Smad7, a natural inhibitor of TGFbeta. These data will help to segregate features of MFS that manifest either structural or regulatory (TGFbeta-related) deficiencies of fibrillin-1. Mouse studies will compare the efficacy of treatment with a beta- adrenergic receptor blocker (that lowers hemodynamic stress) with that for losartan (that both lowers hemodynamic stress and antagonizes TGFbeta) in the treatment of LDS, a devastating disorder associated with vessel rupture and death in early childhood. Results will inform our linkage effort to identify genetic modifiers of the MFS using exceptional pedigrees that show discrete variation in disease manifestations. Taken together, these data will facilitate the development of novel and rational therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR041135-17
Application #
7758192
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Tseng, Hung H
Project Start
1992-03-15
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2012-01-31
Support Year
17
Fiscal Year
2010
Total Cost
$421,488
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Doyle, Jefferson J; Doyle, Alexander J; Wilson, Nicole K et al. (2015) A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome. Elife 4:
Parker, Sarah J; Rost, Hannes; Rosenberger, George et al. (2015) Identification of a Set of Conserved Eukaryotic Internal Retention Time Standards for Data-independent Acquisition Mass Spectrometry. Mol Cell Proteomics 14:2800-13
Fuhrhop, Sara K; McElroy, Mark J; Dietz 3rd, Harry C et al. (2015) High prevalence of cervical deformity and instability requires surveillance in Loeys-Dietz syndrome. J Bone Joint Surg Am 97:411-9
Bertoli-Avella, Aida M; Gillis, Elisabeth; Morisaki, Hiroko et al. (2015) Mutations in a TGF-? ligand, TGFB3, cause syndromic aortic aneurysms and dissections. J Am Coll Cardiol 65:1324-1336
Parker, Sarah J; Raedschelders, Koen; Van Eyk, Jennifer E (2015) Emerging proteomic technologies for elucidating context-dependent cellular signaling events: A big challenge of tiny proportions. Proteomics 15:1486-502
Gallo, Elena M; Loch, David C; Habashi, Jennifer P et al. (2014) Angiotensin II-dependent TGF-? signaling contributes to Loeys-Dietz syndrome vascular pathogenesis. J Clin Invest 124:448-60
Liu, Dongyan; Wang, Connie J; Judge, Daniel P et al. (2014) A Pkd1-Fbn1 genetic interaction implicates TGF-? signaling in the pathogenesis of vascular complications in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 25:81-91
Dietz, Harry (2014) A healthy tension in translational research. J Clin Invest 124:1425-9
Liu, Xiaoqian; Jin, Zhicheng; O'Brien, Richard et al. (2013) Constrained selected reaction monitoring: quantification of selected post-translational modifications and protein isoforms. Methods 61:304-12
van der Linde, Denise; Verhagen, Hence J M; Moelker, Adriaan et al. (2013) Aneurysm-osteoarthritis syndrome with visceral and iliac artery aneurysms. J Vasc Surg 57:96-102

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