Saturated fatty acids involved in DNA damage response, mediated by IRE1a, to promote chemotolerance

饱和游离脂肪酸(FFA)在美国人的饮食中很普遍。最常见的是棕榈酸酯(PA)。血液中游离脂肪酸水平的升高与几种疾病有关。这些疾病包括2型糖尿病、代谢综合征、非酒精性脂肪肝、神经退行性疾病、心脏病和癌症。该项目的总体目标是更清楚地了解PA促进癌细胞存活的分子机制。所获得的洞察力应该会为新的癌症治疗方法的发展提供指导。本科生将从事这项研究。来自代表性不足群体的学生将被积极招募。饱和脂肪酸在激活内质网(ER)压力感应器蛋白和改变DNA损伤修复方面的作用将被调查。具体来说，重点将放在饱和脂肪酸如何参与肌醇需求酶1(IRE1)α的二聚化和激活。IRE1α的激活降低了化疗药物杀死癌细胞的有效性。脂肪酸，如PA，有助于改变膜脂组成，改变膜结构和流动性，影响蛋白质构象和插入脂双层，并影响细胞信号和功能。最近，PI显示PA可以诱导DNA损伤修复，并且阻断PA对IRE1α的激活会使癌细胞对化疗药物敏感。在这里，他们将使用表达野生型(WT)和突变的IRE1DNA蛋白的癌细胞株来研究PA诱导的α损伤修复途径以及IRE1DNA在这一过程中所起的作用。该项目的科学和工程贡献是研究PA和IRE1α之间的生物物理和细胞相互作用，以更清楚地了解PA促进癌细胞存活的分子机制。这些结果可能有助于设计治疗癌症的新型药物制剂。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Saturated free fatty acids (FFA) are prevalent in the American diet. The most common one is palmitate (PA). Elevated levels of FFA in the bloodstream hare linked to several diseases. These include type 2 diabetes, metabolic syndrome, non-alcoholic fatty liver disease, neurodegenerative diseases, heart disease, and cancer. The overall goal of this project is to gain a clearer understanding of the molecular mechanisms by which PA contributes to cancer cell survival. The insights gained should inform the development of new cancer therapeutics. Undergraduate students will be engaged in the research. Students from underrepresented groups will be actively recruited.The role of saturated fatty acids in activating endoplasmic reticulum (ER) stress sensor proteins and altering DNA damage repair will be investigated. Specifically, the focus will be on how saturated fatty acids are involved in the dimerization and activation of inositol-requiring enzyme 1 (IRE1)α. Activation of IRE1α reduces the effectiveness of chemotherapy drugs in killing cancer cells. Fatty acids, such as PA, contribute to changes in the membrane lipid composition, alter the membrane structure and fluidity, affect protein conformation and insertion into the lipid bilayer, and impact cell signaling and function. Recently, the PIs have shown that PA can induce DNA damage repair and that blocking PA activation of IRE1α sensitizes cancer cells to chemotherapy drugs. Here, they will use cancer cell lines expressing wild-type (WT) and mutant IRE1α protein to study the DNA damage repair pathways induced by PA and the role IRE1α plays in this process. The scientific and engineering contribution of this project is the investigation of the biophysical and cellular interactions between PA and IRE1α to gain a clearer understanding of the molecular mechanism by which PA contributes to cancer cell survival. These results could aid the design of novel pharmaceutical agents to treat cancer.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.