User:Wenwatata/sandbox/Statement of Intent

STATEMENT OF INTENT Evaluation of apolipoprotein E genotypes as cholesterol-driven prostate tumor modulators

To this moment, the most unsettled debate about the higher incidence of prostate cancer or the alarming two-fold higher mortality rate of African Americans prostate cancer patients is whether the prevalence of the disease in this group is driven by behavior, biology or both. While pathological characteristics like the higher tumor volumes of African Americans compared to the lower tumor volumes of Caucasians with similar tumor stages strongly suggest that the disease prognosis is driven by biological differences, the disparity in incidence of the disease between second generation US immigrants and their pedigrees with no previous history of prostate cancer strongly implicate the environment or behavior/lifestyle as major risk factors of the disease. In the latter case, adaptations to the so-called western style, red meat-rich diets that consist of dairy products or saturated fats and cholesterol have been associated with these behavioral changes. More confounding is evidence provided by epidemiological and population studies that lifestyle variables alone seldom determine the disparity of prostate cancer risk among different populations. Recent evidence favor a paradigm shift from the sole reliance on genetic or lifestyle variables as risks of disease to the interaction of yet to be identified genetic and lifestyle factors that predispose populations to prostate cancer. There is ample evidence that all direct human ancestors were largely herbivorous, and the shift to meat or cholesterol-rich diets in human ancestors must have selected for genes that modulate both circulating and subcellular cholesterol, for the sake of reducing the risk of slow chronic diseases that reduce health during aging. The selection for this meat-adaptive gene is believed to confer resistance to harmful effects of fats or disease risk associated with meat eating and also increased life expectancy. Apolipoprotein E (apoE) is the major candidate gene that mediates cholesterol and lipid uptake by cells throughout the body. ApoE displays genetic polymorphism with three common alleles, ε2, ε3, and ε4 in a single gene-locus, giving rise to 3 homozygous (apoE2/2, apoE3/3 and apoE4/4) and 3 heterozygous genotypes (apoE2/3, apoE2/4 and apoE3/4). These variants of apoE account for significant genetic variance in cholesterol metabolism than any other gene. ApoE 3 is the most prevalent in all human populations and it is known to have spread during later stages of human evolution, after originating from ancestral apoE4-like gene. ApoE3 is believed to have been selected for its positive effects in cholesterol management and reduction of risk of disease. On the other hand, African and Asian aborigines have notably higher than average levels of apoE4, which is associated with higher totals of blood cholesterol and more oxidized blood lipids. There is mounting evidence that cholesterol deregulation and oxidation are risk factors in various cancers, including cancer of the prostate suggesting that certain apoE genotypes may confer higher risk of prostate cancer. Understandably, these cancer-mediating apoE genotypes could initiate the disease during cholesterol overload, thus suggesting that the disease could be initiated by the interaction of genetic and lifestyle variables. Together, genetic transmission of the highly prevalent apoE4 genotypes between aboriginal Africans and those in the diaspora may influence the vulnerability of African American population to prostate cancer. Our long term goal is predict the susceptibility to prostate cancer, by determining whether some or any apoE genotype(s) are risk factors for the disease, and whether there is an interaction between cholesterol and apoE genotypes to influence the course of the disease. This project has three goals: (1) to examine different apoE isoforms as sentinels of prostate cancer; (2) to identify the relationship between different apoE phenotypes and cholesterol distribution; and (3) to identify the functional relationship between different apoE phenotypes and intracellular cholesterol distribution. To accomplish this, we will determine apoE genotypes of from blood samples of prostate cancer patients from different ethnic backgrounds. Analysis of all the sample genotypes will demonstrate the distribution of apoE alleles in prostate cancer. Also, genotyping information will be used to analyze the similarities and differences in distribution of apo E allele frequencies across samples from ethnic populations studied. We will also investigate whether there is any relationship between plasma cholesterol levels and inherited gene variants of apoE. Finally, we will use transgenic mice expressing human ApoE on null mice background to determine whether apoE isoforms regulate cholesterol homeostasis with the sole aim of determining whether particular apoE genotypes induce prostate cancer by deregulating cholesterol homeostasis.