Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive fatal multisystem disease. The features of SIOD include the invariant findings of skeletal dysplasia, renal failure, and T cell deficiency as well as other symptoms such as adontia, arteriosclerosis, and hypothyroidism. SIOD is caused by loss-of-function mutations in SMARCAL1 (swi/snf related, matrix associated, actin dependent regulator of chromatin, subfamily a-like 1), which encodes a protein with homology to SF2 helicases and SNF2 chromatin remodeling proteins. SMARCAL1 resides in both the nucleus and the cytoplasm. Within the nucleus of Hela cells, SMARCAL1 forms aggregates that frequently co-localize with coilin, a marker of Cajal bodies, and when expressed in Drosophila, it specifically binds euchromatic DNA. Our Drosophila genetic studies have shown that SMARCAL1 is an antagonist of Polycomb group proteins and functions upstream of the trithorax protein BRM. Our observations suggest that SMARCAL1 potentially regulates RNA transcription or processing as a SNF2-related chromatin remodeling protein or as a DNA helicase. To extend the results from our biochemical, cell line, and Drosophila studies to understanding the pathophysiology of SIOD requires a mammalian model. Therefore the objective of this application is to characterize the role of SMARCAL in skeletal development and maintenance through characterization of Smarcal1 expression for wild-type bone development, over-expression of Smarcal1 in bone development, and loss of Smarcal1 expression in bone development. Ultimately our goal is to understand the role of Smarcal1 in mammalian biology, to clarify the human biology underlying SIOD and to use this understanding to ameliorate or treat SIOD and related diseases. The funding provided by this R21 is critical for me, as a new investigator, to develop these murine models. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21DK065725-02
Application #
7140535
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Malozowski, Saul N
Project Start
2005-07-01
Project End
2008-06-30
Budget Start
2006-09-15
Budget End
2008-06-30
Support Year
2
Fiscal Year
2006
Total Cost
$105,462
Indirect Cost
Name
University of British Columbia
Department
Type
DUNS #
251949962
City
Vancouver
State
BC
Country
Canada
Zip Code
V6 1-Z3
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