Noonan syndrome (NS) and related disorders are relatively prevalent autosomal dominant traits with features that include short stature, mental retardation and cardiac abnormalities such as pulmonic stenosis and hypertrophic cardiomyopathy (HCM). Mutations altering RAS/mitogen-activated protein kinase components, usually resulting in gain of function, cause these disorders. Roughly 30% of NS remains unexplained by the known genes. Animal model studies reveal that certain aspects of the """"""""RASopathies"""""""" may be treatable, including HCM.
SPECIFIC AIM 1 will test the hypothesis that additional genes causing NS will reside outside of the central RAS/MAPK pathway, perhaps altering receptor tyrosine kinase metabolism. To test this hypothesis, we will use a genetically unbiased approach toward gene discovery. Unaffected parent-affected child trios will studied with whole genome sequencing to identify novel NS genes. Targeted resequencing will be used with large cohorts to confirm true positives.
In SPECIFIC AIM 2, we hypothesize that candidate therapies for RAF1- related HCM can be identified through screening FDA-approved drugs using a transgenic fruit fly model and that candidate RASopathy therapies identified in fruit flies will prove effective in preventing hypertrophy in mouse models of disease. To test these ideas, we will screen 640 FDA-approved compounds for rescue of pupal lethality in a Raf1 transgenic fly. Hits will be studied for their efficacy curves and for rescue of later developmental phenotypes in several RASopathy fly models. The most promising 10 drugs will then be tested in mice, focusing on HCM in Raf1 mutant mice. Endpoints wil include echocardiographic and histologic parameters.
SPECIFIC AIM 3 's hypothesis is that efficacious lead compounds for treating RAF1-related HCM can be identified through systems pharmacogenomics. We propose to broaden our efforts by screening a larger library of novel compounds, the Maybridge Hitfinder library of 14,400 compounds, using the same Raf1 fly model. We will employ a multidimensional aproach to prioritizing candidate compounds that uses molecular networks derived from genetic and heart gene expression data from mouse and human populations as well as gene expression signatures from NS mouse models before and after the development of HCM as well as its treatment with a MEK inhibitor. By integrating all available data in a network-based context, we will provide a framework for interpreting our chemical compound candidates. We will then test potential efficacy of 50 prioritized compounds in vitro using cardiomyocytes derived from human induced pluripotent stem cells from a RASopathy patient, using regression of hypertrophy as the endpoint. Taken as a whole, the studies proposed in this application will complete (or nearly complete) the project of identifying the range of genes that cause NS when mutated and significantly advance the identification of novel therapeutics for the RASopathies, focusing on HCM. Successful drugs and compounds would likely be useful for most of the RASopathies and for other important clinical aspects such as developmental delays.

Public Health Relevance

Genetic defects altering the RAS-mitogen activated protein kinase (MAPK) cascade, a fundamental signal transduction pathway, cause Noonan syndrome (NS) and related developmental disorders (now termed the RASopathies). Here, we propose to discover additional RASopathy genes and to seek therapies that can reverse the hypertrophic cardiomyopathy associated with these disorders. This work will improve diagnostics for the RASpathies and could result in meaningful therapy for them.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL071207-11
Application #
8440374
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2002-08-01
Project End
2018-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
11
Fiscal Year
2013
Total Cost
$475,742
Indirect Cost
$195,068
Name
Icahn School of Medicine at Mount Sinai
Department
Pediatrics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Talukdar, Husain A; Foroughi Asl, Hassan; Jain, Rajeev K et al. (2016) Cross-Tissue Regulatory Gene Networks in Coronary Artery Disease. Cell Syst 2:196-208
Miller, Clint L; Pjanic, Milos; Wang, Ting et al. (2016) Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci. Nat Commun 7:12092
Franzén, Oscar; Ermel, Raili; Cohain, Ariella et al. (2016) Cardiometabolic risk loci share downstream cis- and trans-gene regulation across tissues and diseases. Science 353:827-30
Sanderson, Saskia C; Linderman, Michael D; Suckiel, Sabrina A et al. (2016) Motivations, concerns and preferences of personal genome sequencing research participants: Baseline findings from the HealthSeq project. Eur J Hum Genet 24:14-20
Stevenson, David A; Schill, Lisa; Schoyer, Lisa et al. (2016) The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway. Am J Med Genet A 170:1959-66
Quintero-Rivera, Fabiola; Xi, Qiongchao J; Keppler-Noreuil, Kim M et al. (2015) MATR3 disruption in human and mouse associated with bicuspid aortic valve, aortic coarctation and patent ductus arteriosus. Hum Mol Genet 24:2375-89
Mulero-Navarro, Sonia; Sevilla, Ana; Roman, Angel C et al. (2015) Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia. Cell Rep 13:504-515
Cordeddu, Viviana; Yin, Jiani C; Gunnarsson, Cecilia et al. (2015) Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome. Hum Mutat 36:1080-7
Gelb, Bruce D; Roberts, Amy E; Tartaglia, Marco (2015) Cardiomyopathies in Noonan syndrome and the other RASopathies. Prog Pediatr Cardiol 39:13-19
Edwards, Jonathan J; Martinelli, Simone; Pannone, Luca et al. (2014) A PTPN11 allele encoding a catalytically impaired SHP2 protein in a patient with a Noonan syndrome phenotype. Am J Med Genet A 164A:2351-5

Showing the most recent 10 out of 48 publications