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

在美国，生活在低收入社区的人经常无法获得负担得起的住房。 健康食品（“食物沙漠”）。生活在食物沙漠中的人们必须依靠便利店和快餐 连锁店提供很少的健康食品选择，如水果和蔬菜。超市的失败 连锁店在市中心社区开设提供新鲜水果和蔬菜的商店， 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有色人种青年妇女（非裔美国人和拉丁裔/西班牙裔） 美国人）比欧美人更有可能生活在食物沙漠中。缺乏 健康的食物选择使年轻的有色人种女性患2型糖尿病、肥胖和三重糖尿病的风险增加， 阴性乳腺癌（TNBC）。虽然肥胖、糖尿病和TNBC是不同的疾病，但它们不会发生在 与世隔绝肥胖是TNBC的重要风险因素，胰岛素促进许多信号通路， 定义TNBC的侵略性生物学。在我们位于洛杉矶的City of Hope诊所， 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测试 生活在洛杉矶食物沙漠邮政编码的有色人种女性，胰岛素抵抗是否会促进表观遗传 并增加TNBC风险。当细胞停止对胰岛素作出反应时，就会发生胰岛素抵抗。每次 患有胰岛素抵抗的妇女进食时，血清胰岛素峰值达到正常值的5-10倍（高胰岛素血症）。胰岛素 驱动线粒体呼吸，增加生物活性代谢物的产生，如乙酰辅酶A （乙酰辅酶A）。高胰岛素血症过度驱动线粒体电子传递链， 产生生物活性代谢物，如乙酰辅酶A。最近的证据表明，过量生产乙酰基- 辅酶A使组蛋白过度乙酰化，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1）将使循环胰岛素水平正常化， 乙酰辅酶A生产，但2）不会逆转表观遗传损伤。目标1将描述环境特征， 生活在希望之城集水区的妇女食物沙漠邮政编码。目标2将测试胰岛素驱动的 线粒体功能障碍增加染色质可接近性和基因组不稳定性。Aim 3将进行调查 与胰岛素抵抗相关的胰岛素驱动的表观遗传损伤是否会被二甲双胍逆转。 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伤，但不能 逆转表观遗传损伤一旦发生-重要的是建立早期积极的治疗前， 我们的目标是在TNBC高风险妇女中开展糖尿病研究，并积极制定公共政策，以结束食物沙漠。

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.