The three PROJECTS in this Program will integrate transcriptional networks with cellular, molecular, electrophysiological, and physiological mechanisms that underlie dysphagia in mouse models of 22q11 Deletion Syndrome (22q11DS). CORE C, the Genomics and Bioinformatics Core, will generate high-quality cDNA libraries and RNA-Seq reads from RNA isolated from specific brain regions and nuclei, known to be important for feeding and swallowing, using specimens isolated from mouse genetic models of 22q11DS. The resulting RNA-Seq pair-end reads will be processed by our bioinformatics pipeline to generate the following genomics resources: i) assembly of reads into transcripts and alternatively spliced transcripts; ii) assembly of non-coding RNAs; iii) differential expression analysis; and iv) gene network and pathway over-representation analysis. These genomics resources serve two major roles. First, this information will serve to validate or invalidate hypotheses being tested in the Program PROJECTS. Second, we anticipate that our bioinformatics approach will generate new foundations, not envisioned or anticipated a priori at the Program's outset, for additional hypothesis testing at the molecular, physiological, and pharmacological (e.g., drug targeting of pathways to ameliorate disrupted feeding behavior) levels. Moreover, the genomics resources generated by CORE C will be deposited into a central repository (e.g., Sequence Read Archive of NCBI) for Data Sharing with other investigational groups, allowing them to mine our data and generate their own testable hypotheses. NARRATIVE CORE C will process and assess RNA-Seq transcriptome data for all 3 PROJECTS using an integrated computational pipeline. We will facilitate testing specific hypotheses defined in PROJECTS 1 and 2, as well as generate hypotheses that provide a framework for further analysis of molecular, cellular, and physiological mechanisms that underlie pediatric dysphagia (PROJECT 1), its developmental origin (PROJECT 2), or prevention (PROJECT 3). Our computational approach is anticipated to identify new diagnostic signatures or high priority pharmacologically accessible targets for intervention testing in animal models.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD083157-05
Application #
9666796
Study Section
National Institute of Child Health and Human Development Initial Review Group (CHHD)
Project Start
Project End
2021-02-28
Budget Start
2019-03-01
Budget End
2020-02-28
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
George Washington University
Department
Type
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
Wang, Xin; Bryan, Corey; LaMantia, Anthony-Samuel et al. (2017) Altered neurobiological function of brainstem hypoglossal neurons in DiGeorge/22q11.2 Deletion Syndrome. Neuroscience 359:1-7
Karpinski, Beverly A; Bryan, Corey A; Paronett, Elizabeth M et al. (2016) A cellular and molecular mosaic establishes growth and differentiation states for cranial sensory neurons. Dev Biol 415:228-241
Baker, Jennifer L; Wood, Bernard; Karpinski, Beverly A et al. (2016) Testicular receptor 2, Nr2c1, is associated with stem cells in the developing olfactory epithelium and other cranial sensory and skeletal structures. Gene Expr Patterns 20:71-9
LaMantia, Anthony-Samuel; Moody, Sally A; Maynard, Thomas M et al. (2016) Hard to swallow: Developmental biological insights into pediatric dysphagia. Dev Biol 409:329-42
Meechan, Daniel W; Maynard, Thomas M; Tucker, Eric S et al. (2015) Modeling a model: Mouse genetics, 22q11.2 Deletion Syndrome, and disorders of cortical circuit development. Prog Neurobiol 130:1-28
Paronett, Elizabeth M; Meechan, Daniel W; Karpinski, Beverly A et al. (2015) Ranbp1, Deleted in DiGeorge/22q11.2 Deletion Syndrome, is a Microcephaly Gene That Selectively Disrupts Layer 2/3 Cortical Projection Neuron Generation. Cereb Cortex 25:3977-93