The applkicant is a senior clinical genetics fellow who has completed his clinical training. His long-term objective is to become an independent physician scientist focused on studying genetic disorders that impact the health of children. This application will provide the candidate with training in developmental biology, new technologies in human genetics, and mouse genetics. The overall scientific goal is to identify and characterize genes responsible for congenital diaphragmatic hernia (CDH). CDH is a developmental abnormality in which regions of the diaphragm fail to form, allowing the contents of the abdominal cavity to invade the space normally reserved for the developing lung. CDH affects approximately 1 in 2,500 newborns. Mortality ranges from 30 to 60%, and infants who survive often have significant morbidity from pulmonary hypoplasia and pulmonary hypertension.
Specific aims for this study include: 1) establishing a collaborative DNA repository for the study of CDH, 2) screening candidate genes for CDH-causing mutations, 3) identifying and mapping chromosomal regions involved in CDH using novel comparative genomic hybridization (CGH) technology, and 4) characterizing a mouse model of CDH. Candidate genes, selected based on chromosome position and putative function, will be screened for CDH-causing mutation by direct sequencing. DNA from individuals with CHD will be screened for abnormalities by G-banded chromosome analysis and CGH using a genome-wide microarray of over 20,000 overlapping clones with a approximately 300 kb resolution. A CDH mouse model that mimics the most common form of CDH in human has been developed by selective ablation of COUP-TFII, a gene for transcription factor regulated by the retinoic acid pathway. The candidate will characterize these mice by determining the effect of COUP-TFII ablation on diaphragm musculature, innervation, cellular proliferation, as well as apoptosis. Identifying and characterizing the genes that cause CDH may lead to the development of new preventative and therapeutic strategies, and will provide insight into the molecular basis of diaphragm development.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HD050583-02
Application #
7118153
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Coulombe, James N
Project Start
2005-09-05
Project End
2010-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
2
Fiscal Year
2006
Total Cost
$129,828
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Wat, Margaret J; Beck, Tyler F; Hernandez-Garcia, Andres et al. (2012) Mouse model reveals the role of SOX7 in the development of congenital diaphragmatic hernia associated with recurrent deletions of 8p23.1. Hum Mol Genet 21:4115-25
Wat, Margaret J; Veenma, Danielle; Hogue, Jacob et al. (2011) Genomic alterations that contribute to the development of isolated and non-isolated congenital diaphragmatic hernia. J Med Genet 48:299-307
Wat, Margaret J; Enciso, Victoria B; Wiszniewski, Wojciech et al. (2010) Recurrent microdeletions of 15q25.2 are associated with increased risk of congenital diaphragmatic hernia, cognitive deficits and possibly Diamond--Blackfan anaemia. J Med Genet 47:777-81
Qidwai, Kanwal; Pearson, David M; Patel, Gayle Simpson et al. (2010) Deletions of Xp provide evidence for the role of holocytochrome C-type synthase (HCCS) in congenital diaphragmatic hernia. Am J Med Genet A 152A:1588-90
Wat, Margaret J; Shchelochkov, Oleg A; Holder, Ashley M et al. (2009) Chromosome 8p23.1 deletions as a cause of complex congenital heart defects and diaphragmatic hernia. Am J Med Genet A 149A:1661-77
Klaassens, M; Galjaard, R J H; Scott, D A et al. (2007) Prenatal detection and outcome of congenital diaphragmatic hernia (CDH) associated with deletion of chromosome 15q26: two patients and review of the literature. Am J Med Genet A 143A:2204-12
Holder, A M; Klaassens, M; Tibboel, D et al. (2007) Genetic factors in congenital diaphragmatic hernia. Am J Hum Genet 80:825-45
Scott, Daryl A (2007) Genetics of congenital diaphragmatic hernia. Semin Pediatr Surg 16:88-93
Scott, Daryl A; Klaassens, Merel; Holder, Ashley M et al. (2007) Genome-wide oligonucleotide-based array comparative genome hybridization analysis of non-isolated congenital diaphragmatic hernia. Hum Mol Genet 16:424-30
Klaassens, M; Scott, D A; van Dooren, M et al. (2006) Congenital diaphragmatic hernia associated with duplication of 11q23-qter. Am J Med Genet A 140:1580-6