The applicant is a clinical genetics fellow with previous broad clinical experience. The goal of this proposal is for him to become an independent clinical investigator in the genetic dissection of complex diseases, through graduate level courses and mentored research. Specific courses will include molecular genetics, genetic epidemiology, research study design, and ethical conduct of scientific research. The research setting will be the Baylor College of Medicine, a center of excellence in genetic research. Facilities include a genotyping center and a sequencing center affiliated with the Human Genome Project. Mentored research will be performed on the genetics of the left ventricular outflow tract obstruction (LVOTO) subgroup of congenital cardiovascular malformations (CCVM). This group accounts for ~20% of all CCVM and are important contributors to overall neonatal mortality. Various lines of embryological, epidemiological, and cytogenetic evidence point to the importance of genetic factors, but most cases are sporadic, indicating the genetic components are complex and do not conform to a simple pattern of inheritance. The first Specific Aim is to investigate LVOTO genetics by the linkage approach on multiplex LVOTO families and affected sib pairs. The second Specific Aim is to study family members of affected cases by echocardiography, to search for quantitative measurements that might be useful for mapping quantitative trait loci contributing to left heart development. The third Specific Aim is to establish and test affected-child/parent trios in association studies by transmission dysequilibrium and likelihood ratio analyses. Approximately 50 candidate genes, suggested primarily by mouse knockout phenotypes, will be examined in over 300 samples. The fourth Specific Aim will be to screen for mutations in candidate genes identified through animal models in the literature or identified by our linkage and association studies above. The proposed studies will launch the applicant on an independent research career, providing a base on which to advance genetic analyses of CCVM with the aim to reduce their occurrence and provide new treatment opportunities.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
7K23HL070823-03
Application #
6956047
Study Section
Special Emphasis Panel (ZHL1-CSR-J (F1))
Program Officer
Jaquish, Cashell E
Project Start
2003-04-01
Project End
2008-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
3
Fiscal Year
2005
Total Cost
$131,484
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
Klima, Jennifer; Fitzgerald-Butt, Sara M; Kelleher, Kelly J et al. (2014) Understanding of informed consent by parents of children enrolled in a genetic biobank. Genet Med 16:141-8
Lalani, Seema R; Ware, Stephanie M; Wang, Xueqing et al. (2013) MCTP2 is a dosage-sensitive gene required for cardiac outflow tract development. Hum Mol Genet 22:4339-48
McBride, Kim L; Zender, Gloria A; Fitzgerald-Butt, Sara M et al. (2011) Association of common variants in ERBB4 with congenital left ventricular outflow tract obstruction defects. Birth Defects Res A Clin Mol Teratol 91:162-8
Riley, Maurisa F; McBride, Kim L; Cole, Susan E (2011) NOTCH1 missense alleles associated with left ventricular outflow tract defects exhibit impaired receptor processing and defective EMT. Biochim Biophys Acta 1812:121-9
McBride, Kim L; Zender, Gloria A; Fitzgerald-Butt, Sara M et al. (2009) Linkage analysis of left ventricular outflow tract malformations (aortic valve stenosis, coarctation of the aorta, and hypoplastic left heart syndrome). Eur J Hum Genet 17:811-9
McBride, Kim L; Riley, Maurisa F; Zender, Gloria A et al. (2008) NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling. Hum Mol Genet 17:2886-93
McBride, Kim L; Belmont, John W; O'Brien, William E et al. (2007) Heritability of plasma amino acid levels in different nutritional states. Mol Genet Metab 90:217-20
Schwaderer, Andrew L; Bates, Carlton M; McHugh, Kirk M et al. (2007) Renal anomalies in family members of infants with bilateral renal agenesis/adysplasia. Pediatr Nephrol 22:52-6
Yang, Yan; Chung, Erwin K; Wu, Yee Ling et al. (2007) Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European America Am J Hum Genet 80:1037-54
McBride, Kim L; Marengo, Lisa; Canfield, Mark et al. (2005) Epidemiology of noncomplex left ventricular outflow tract obstruction malformations (aortic valve stenosis, coarctation of the aorta, hypoplastic left heart syndrome) in Texas, 1999-2001. Birth Defects Res A Clin Mol Teratol 73:555-61

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