Trisomy 21 (Down syndrome, DS), is among the most complicated genetic situations compatible with substantial survival. The clinical presentation of DS represents the interaction of many triplicated genes throughout development. Understanding what individual genes do is a necessary component of approaches to therapy for features of Down syndrome, but it is not sufficient. The earlier periods of this award focused on creating and characterizing animal models in which to study DS, supporting assessment of all tissues at all stages of life. In the last award period we used these models and principles to make three significant advances. First, we determined that trisomic mice recapitulate (and predict) structural problems observed in the very small DS cerebellum, defined the timing, cell type, process and growth factor (SHH) responsible for this hypocellularity and then cured it in mice. Second, we provided the first experimental evidence that DS is a neurocristopathy by showing that the craniofacial hypoplasia in DS and in mouse models originates with problems in delamination, migration and proliferation of neural crest cells (NCC) in the first pharyngeal arch. Third, we provided biological evidence to answer a 50 year old statistical argument that people with DS get substantially (90%) less cancer than do euploid individuals and identified a single gene, Ets2, dosage for which is inversely correlated with intestinal tumor number in a model of colon cancer. Because NCC and SHH each affect many (overlapping) aspects of development, we will test the hypothesis that they represent """"""""common denominators"""""""" of DS phenotypes. We will use a pharmacological approach to """"""""cure"""""""" the NCC deficit leading to craniofacial hypoplasia. We have begun a survey of the entire Hsa21 gene set to determine gene dosage effects on early development in zebrafish. We will further characterize gene expression with regard to nuclear compartmentalization, a newly appreciated epigenetic regulatory mechanism. We will define more precisely the mechanism of Ets2 tumor repression, and screen for drugs that might act on this pathway as a prophylactic for cancer in everyone, regardless of ploidy.

Public Health Relevance

Determining how Down syndrome is caused is essential to treat it, so we will use several methods to understand gene effects. We will use information from the last award to ameliorate the characteristic facial appearance in DS mice. People with DS get less cancer and may have fewer strokes and heart attacks, we will determine why that is and apply that information to prevention of these serious health problems in all.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD038384-12
Application #
8233965
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Oster-Granite, Mary Lou
Project Start
2000-03-01
Project End
2016-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
12
Fiscal Year
2012
Total Cost
$556,471
Indirect Cost
$192,953
Name
Johns Hopkins University
Department
Physiology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Xiao, Mei-Fang; Xu, Desheng; Craig, Michael T et al. (2017) NPTX2 and cognitive dysfunction in Alzheimer's Disease. Elife 6:
Starbuck, John M; Cole 3rd, Theodore M; Reeves, Roger H et al. (2017) The Influence of trisomy 21 on facial form and variability. Am J Med Genet A 173:2861-2872
Xiang, Jianxing; Yang, Su; Xin, Ning et al. (2017) DYRK1A regulates Hap1-Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome. Proc Natl Acad Sci U S A 114:E1224-E1233
Baab, Karen L; Brown, Peter; Falk, Dean et al. (2016) A Critical Evaluation of the Down Syndrome Diagnosis for LB1, Type Specimen of Homo floresiensis. PLoS One 11:e0155731
Yang, Annan; Currier, Duane; Poitras, Jennifer L et al. (2016) Increased Skin Tumor Incidence and Keratinocyte Hyper-Proliferation in a Mouse Model of Down Syndrome. PLoS One 11:e0146570
Potier, Marie-Claude; Reeves, Roger H (2016) Editorial: Intellectual Disabilities in Down Syndrome from Birth and Throughout Life: Assessment and Treatment. Front Behav Neurosci 10:120
Singh, Nandini; Dutka, Tara; Reeves, Roger H et al. (2016) Chronic up-regulation of sonic hedgehog has little effect on postnatal craniofacial morphology of euploid and trisomic mice. Dev Dyn 245:114-22
Burnicka-Turek, Ozanna; Steimle, Jeffrey D; Huang, Wenhui et al. (2016) Cilia gene mutations cause atrioventricular septal defects by multiple mechanisms. Hum Mol Genet 25:3011-3028
Li, Huiqing; Edie, Sarah; Klinedinst, Donna et al. (2016) Penetrance of Congenital Heart Disease in a Mouse Model of Down Syndrome Depends on a Trisomic Potentiator of a Disomic Modifier. Genetics 203:763-70

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