Identifying genetic variants that significantly alter the function of critical proteins provides insights into related disease processes and possible therapies. The low density lipoprotein receptor (LDLR) is remarkable in this regard because LDLR mutations are a primary cause of familial hypercholesterolemia, i.e., loss of a single LDLR allele causes an approximately 100% increase in LDL-cholesterol levels. Although LDLR SNPs and their haplotypes have been associated with altered cholesterol levels, specific SNPs that alter LDLR function have not been identified. Functional LDLR variants may provide insights into diseases that may be associated with increased cholesterol, e.g., Alzheimer's Disease (AD). Indeed, a robust genetic factor for both cholesterol and AD is the apoE4 allele of the apoE gene. Although apoE is implicated in amyloid-beta (Abeta) deposition in Alzheimer's disease, apoE is known more widely for its role in cholesterol delivery and homeostasis; apoE4 is associated with increased LDL-cholesterol via its role as a ligand for the LDL family of cell surface receptors that mediate lipoprotein uptake. This proposal focuses on the global hypothesis that SNPs that modulate LDLR splicing or expression, and the haplotypes defined by these functional SNPs, are associated with altered cholesterol homeostasis and Alzheimer's disease. Hence, we propose the following Specific Aims: 1. Evaluate LDLR SNPs to identify those that alter LDLR splicing and /or expression, 2. Evaluate the expression and function of LDLR proteins resulting from alternative LDLR splicing. 3. Evaluate LDLR genotypes and haplotypes for their association with cholesterol homeostasis and Alzheimer's disease. Overall, this focused approach will directly evaluate the hypothesis that LDLR polymorphisms modulate LDLR splicing and expression to increase LDL-cholesterol and Alzheimer's disease odds. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG026147-02
Application #
7272847
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Miller, Marilyn
Project Start
2006-08-15
Project End
2010-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$262,752
Indirect Cost
Name
University of Kentucky
Department
Physiology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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