Human chromosome 21 (HC21) harbors genes which is believed to be associated with a number of neurological diseases, including amyotrophic lateral sclerosis (ALS 1), familial Alzheimer disease (FAD), and Down syndrome (DS). Among these, DS constitutes the most common disease resulting from partial or total trisomy of HC21. DS is characterized by a number of pathological consequences the most important of which result in precocious aging often accompanied by signs of Alzheimer disease (AD). Several early observations indicated that a small HC21 segment (Down syndrome critical region or DSCR) containing a restricted number of genetic elements may be responsible for most of the Down symptoms. Other regions of HC21 and even some genes present on heterologous diploid chromosomes may also contribute to the complex phenotype of DS either through compensatory or additive interactions. This is presumed to be especially true for genes which code for antioxidant enzymes and which are dispersed throughout the nuclear genome. This has particular relevance in view of the fact that trisomy of HC21 leads to an overexpression of at least two enzymes which are implicated in the production and metabolism of reactive oxygen species (ROS), viz., superoxide dismutase (SOD I) and carbonyl reductase (CBR). In the absence of compensatory support from other antioxidant genes located on heterologous chromosomes (such as glutathione peroxidase and catalase genes), trisomy of HC21 may lead to an accumulation of highly reactive hydroxyl radicals which could severely damage the functional integrity of the cell. One important consequence of such a situation would be lesions in mitochondrial DNA that is especially vulnerable to oxidative injury. The major goals of the present project are to (A) examine the interactions between some of the the key genes of trisomic CH21 and other chromosomal genes, and (B) to verify if antioxidants such as coenzyme Q, vitamin E and ascorbic acid, individually or in combination, could play a positive role in at least partially restoring the normal functioning of trisomic HC21 cells.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD039038-04
Application #
6643322
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Oster-Granite, Mary Lou
Project Start
2000-07-10
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
4
Fiscal Year
2003
Total Cost
$207,715
Indirect Cost
Name
Brain Insights, Inc.
Department
Type
DUNS #
120450775
City
Irvine
State
CA
Country
United States
Zip Code
92614