The current proposal seeks activation of the ROO phase of a K99R00 award (1K99/ROO-DE018954). The PI has fulfilled the career goals and research aims planned for the K99 phase and is ready to move to an independent position in the ROO phase. The institutional support and environment have been instrumental for the Pi's achievements. The experimental focus of this proposal is on MMP gene variants and cleft lip with or without cleft palate (CL/P). CL/P is a common congenital anomaly that results from defects during embryonic development. The etiology of CL/P is multifactorial with multiple genetic and environmental factors assumed to be responsible. MMP genes play a significant role in the tissue remodeling required during embryonic development and may be involved in CL/P etiology. The study hypothesis is that imbalances in gene transcription due to DNA polymorphisms may alter the rates of extracellular matrix synthesis and degradation (and thus tissue remodeling) during craniofacial development and hence predispose to oral clefts. The experiments planned for the ROD follow-up on results obtained during the K99 phase of this award. Briefly, the Specific Aim. is to investigate the biological effects of the polymorphisms associated with CL/P in the K99 phase with regards to a potential role in CL/P etiology. Special emphasis wil be ?iven to polymorphisms in the gene promoters for their ability to regulate gene expression. Two experimental approaches will be used. Transient transfection will be used to afsess allele-dependent gene functional activity. Electrophoretic mobility shift assays (EMSA) will be used to verify protein/DNA interactions vwthin a given gene's upstream regulatory region. Understanding the functionality of disease-associated SNPs is an . important complementation and validation for genetic association studies. In the context of this proposal, any associated polymorphism that is revealed functional may provide important insights into the etiology of CL/P, and different perspectives for future research in the long-term. The proposed study constitutes ari innovative field of research adn confonns to.the initiatives of the NIH mission for future treatment possibilities.

Public Health Relevance

Cleft lip/palate (CL/P) id a congenital anomaly that results from defects during embryonic development and implies lifelong^medlcal interventions. MMP geries play a significant role during embryonic development and may be involved in CL/P etiology. This proposal seeks to investigate the biological effects of genetic variations in MMP genes for potential roles in CL/P. If the hypothesis is confirmed it will greatly contribute to an improved understanding of CL/P etiology.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Transition Award (R00)
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Study Section
Special Emphasis Panel (NSS)
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Harris, Emily L
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University of Texas Health Science Center Houston
Schools of Dentistry
United States
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Fontoura, Clarissa; Silva, Renato M; Granjeiro, José M et al. (2015) Association of WNT9B Gene Polymorphisms With Nonsyndromic Cleft Lip With or Without Cleft Palate in Brazilian Nuclear Families. Cleft Palate Craniofac J 52:44-8
Letra, Ariadne; Maili, Lorena; Mulliken, John B et al. (2014) Further evidence suggesting a role for variation in ARHGAP29 variants in nonsyndromic cleft lip/palate. Birth Defects Res A Clin Mol Teratol 100:679-85
Letra, A; Zhao, M; Silva, R M et al. (2014) Functional Significance of MMP3 and TIMP2 Polymorphisms in Cleft Lip/Palate. J Dent Res 93:651-6
Letra, Ariadne; Silva, Renato M; Motta, Luise G et al. (2012) Association of MMP3 and TIMP2 promoter polymorphisms with nonsyndromic oral clefts. Birth Defects Res A Clin Mol Teratol 94:540-8
Fontoura, Clarissa; Silva, Renato M; Granjeiro, Jose M et al. (2012) Further evidence of association of the ABCA4 gene with cleft lip/palate. Eur J Oral Sci 120:553-7
Letra, Ariadne; Silva, Renato M; Rylands, Ryan J et al. (2012) MMP3 and TIMP1 variants contribute to chronic periodontitis and may be implicated in disease progression. J Clin Periodontol 39:707-16
Andia, Denise Carleto; Letra, Ariadne; Casarin, Renato Correa Viana et al. (2012) Genetic analysis of the IL8 gene polymorphism (rs4073) in generalized aggressive periodontitis. Arch Oral Biol :
Letra, A; Bjork, B; Cooper, M E et al. (2012) Association of AXIN2 with non-syndromic oral clefts in multiple populations. J Dent Res 91:473-8
Andia, Denise C; de Oliveira, Naila F P; Letra, Ariadne M et al. (2011) Interleukin-8 gene promoter polymorphism (rs4073) may contribute to chronic periodontitis. J Periodontol 82:893-9
Letra, Ariadne; Menezes, Renato; Cooper, Margaret E et al. (2011) CRISPLD2 variants including a C471T silent mutation may contribute to nonsyndromic cleft lip with or without cleft palate. Cleft Palate Craniofac J 48:363-70

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