A major unsolved question in the genetic epidemiology of late life diseases such as atherosclerosis and Alzheimer disease is why the deleterious APOE epsilon4 allele emerged in our progenitors. Our thesis (Martin, Neurobiology of Aging 2:441-443, 1999) is that this allele was selected for resistance to infection by lipophylic pathogens. In this proposal, we test a specific candidate organism, Trypanosoma brucei brucei, a protozoan that is the cause of endemic infections in many regions of Africa and is associated with a high mortality rate when infections involve the brain (African sleeping sickness). As an initial approach to this hypothesis, we propose to follow the kinetics of replication of T. brucei in the blood stream of experimentally infected transgenic C57Bl/6 mice that have been engineered to express either the human APOE epsilon3 or epsilon4 alleles at the sites of their endogenous APOE loci (""""""""knockin"""""""" mice). We predict an increasing gradient of susceptibility to challenge w ith T. brucei, from the relatively resistant strains of mice homozygous for epsilon4, to heterozygotes (epsilon3/epsilon4), to highly susceptible epsilon3 homozygotes. If the hypothesis is supported, future directions could include extensions of the experiments to other APOE alleles (e.g., APOE epsilon 4 and, as they are being defined by our group in another study, various human haplotypes), studies of the mechanisms of resistance to infection, and epidemiological studies in human populations, in which the role of various APOE haplotypes in conferring resistance to T. brucei can be tested.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Research Grants (R03)
Project #
1R03AG019033-01
Application #
6287203
Study Section
Special Emphasis Panel (ZAG1-PCR-5 (O2))
Program Officer
Fuldner, Rebecca A
Project Start
2001-05-01
Project End
2003-04-30
Budget Start
2001-05-01
Budget End
2003-04-30
Support Year
1
Fiscal Year
2001
Total Cost
$76,000
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195