Epigenetic damage in women living in LA food-desert zip codes

在美国，居住在低收入社区的人经常无法负担得起 健康食品(“食品沙漠”)。生活在食物沙漠中的人们必须依赖便利店和快餐 几乎不提供健康食品选择的连锁店，如水果和蔬菜。超级市场的失败 在市中心社区找到提供新鲜水果和蔬菜的连锁店--一种食物形式 红线-对我们许多公民的营养、健康和福祉产生了深远的影响， 尤其是年轻的有色人种男女。有色人种年轻女性(非裔美国人和拉丁裔/西班牙裔- 美国人)比他们的欧美同行更有可能生活在食物沙漠中。缺乏 选择健康的食物会增加有色人种年轻女性患2型糖尿病、肥胖症和三重糖尿病的风险 阴性乳腺癌(TNBC)。虽然肥胖、糖尿病和TNBC是不同的疾病，但它们并不会发生 与世隔绝。肥胖是TNBC的重要危险因素，胰岛素促进许多信号通路， 定义TNBC的侵略性生物学。在我们洛杉矶的希望之城诊所，37%的年轻女性 患有TNBC高风险的有色人种也有糖尿病前期(胰岛素抵抗)。在这里，我们的目标是在年轻的 生活在洛杉矶食品沙漠邮政编码的有色人种女性，胰岛素抵抗是否促进表观遗传 损害和增加TNBC风险。当细胞停止对胰岛素的反应时，就会发生胰岛素抵抗。每次 患有胰岛素抵抗的女性进食后，血清胰岛素会飙升至正常水平的5-10倍(高胰岛素血症)。胰岛素 促进线粒体呼吸，增加乙酰辅酶A等生物活性代谢物的产生 (乙酰辅酶A)。高胰岛素血症使线粒体电子传输链超载，并导致过度 产生生物活性代谢物，如乙酰辅酶A。最近的证据表明，过量生产的乙酰- 辅酶A高乙酰化组蛋白，促进不适当的染色质开放和长期 表观遗传损伤。我们假设二甲双胍将使循环中的胰岛素水平正常化，并降低 但是，2)乙酰辅酶A的产生不会逆转表观遗传损伤。目标1将描述环境和 生活在希望之城集水区食品-沙漠邮政编码的妇女。Aim 2将测试胰岛素驱动的 线粒体功能障碍增加了染色质的可及性和基因组的不稳定性。AIM 3将调查 与胰岛素抵抗相关的胰岛素驱动的表观遗传损害是否会被二甲双胍逆转。 重要意义：如果我们的假设是正确的--我们只能防止新的表观遗传损害，但不能 一旦发生表观遗传损害就逆转-重要的是早期积极治疗Pre-Pre 在TNBC的高危妇女中进行糖尿病治疗，并积极制定公共政策，以结束粮食荒漠。

In the United States, people living in low-income neighborhoods frequently do not have access to affordable healthy food (“food-deserts”). People living in food-deserts must rely on convenience stores and fast-food chains that offer few, if any, healthy food choices, such as fruits and vegetables. The failure of supermarket chains to locate stores that offer fresh fruits and vegetables in inner-city communities—a form of food redlining—has had a profound impact on the nutrition, health, and well-being of many of our citizens, particularly young Men- and Women-of-Color. Young Women-of-Color (African-American and Latina/Hispanic- American) are more likely to live in food-deserts than their European-American counterparts. The lack of healthy food choices puts young Women-of-Color at increased risk for type-2 diabetes, obesity, and triple- negative breast cancer (TNBC). Although obesity, diabetes, and TNBC are distinct diseases, they do not occur in isolation. Obesity is a significant risk factor for TNBC and insulin promotes many signaling pathways that define the aggressive biology of TNBC. At our City of Hope Clinics in Los Angeles, 37% of young Women-of- Color who are at high risk for TNBC also have pre-diabetes (insulin resistance). Here we aim to test in young Women-of-Color living in food-desert zip codes in Los Angeles, whether insulin-resistance promotes epigenetic damage and increases TNBC-risk. Insulin resistance occurs when cells stop responding to insulin. Every time a woman with insulin-resistance eats, serum insulin spikes to 5-10 times normal (hyperinsulinemia). Insulin drives mitochondrial respiration and increases production of bioactive metabolites such as acetyl-coenzyme A (acetyl-CoA). Hyperinsulinemia overdrives the mitochondrial electron transport chain and drives excessive production of bioactive metabolites, such as acetyl-CoA. Recent evidence shows that overproduction of acetyl- CoA hyper-acetylates histone proteins and promotes inappropriate chromatin opening and long-term epigenetic damage. We hypothesize that metformin 1) will normalize circulating insulin levels and reduce acetyl-CoA production but, 2) will not reverse epigenetic damage. Aim 1 will characterize the environment and women living in City of Hope catchment area food-desert zip codes. Aim 2 will test whether insulin-driven mitochondrial dysfunction increase chromatin accessibility and genomic instability. Aim 3 will investigate whether insulin-driven epigenetic damage associated with insulin-resistance will be reversed by metformin. Significance: If our hypothesis is correct — that we can only prevent new epigenetic damage, but cannot reverse epigenetic damage once it occurs — it is important to institute early aggressive treatment of pre- diabetes in women at high-risk for TNBC and work aggressively to enact public policy to end food-deserts.