Dissecting the molecular mechanisms underlying lipotoxicity in the kidney.

摘要 慢性肾脏疾病影响着世界各地的数百万人。遗传和环境因素的结合 可能会导致肾脏疾病的进展。肥胖是2型等代谢性疾病的危险因素 糖尿病(T2D)，它与肾脏疾病的进展高度相关。T2D经常被描述为 血液中的高水平脂质会对肾脏等非脂肪组织产生毒性。这个 随之而来的脂肪毒性可能会损害肾脏细胞，导致糖尿病等疾病的发病。 肾病，但脂肪毒性在肾脏中的具体细胞效应尚不清楚。第一个目标是确定 哪些脂肪酸对肾小管上皮细胞有脂毒性，以及它们诱导了什么细胞应激反应，使用 读出方法如内质网应激、细胞存活率和转录组分。第二个目标将使用扰动序列，它 将CRISPR筛查与单细胞RNA测序相结合，以识别其扰动诱导的基因 细胞应激状态的转录签名，随后在肾脏器官中进行验证。最终，这些 实验将揭示介导FFA诱导的肾细胞脂毒损伤的基因和途径。vt.给出 肾脏疾病治疗的需求在很大程度上尚未得到满足，我们的研究将为揭示新的靶点提供一步 以及扩大我们对肾脏疾病基本机制的了解。

Abstract Chronic kidney diseases affect millions around the world. A combination of genetic and environmental factors can contribute to the progression of kidney disease. Obesity is a risk factor for metabolic diseases like type 2 diabetes (T2D), which has been highly associated with kidney disease progression. T2D is often characterized by high levels of lipids in the bloodstream, which can be toxic to non-adipose tissues like the kidney. The consequent lipotoxicity may injure kidney cells, contributing to the pathogenesis of diseases like diabetic nephropathy, but the specific cellular effects of lipotoxicity in the kidney are unknown. The first aim will identify which FFAs are lipotoxic to kidney tubular epithelial cells and what cellular stress responses they induce, using readout methods like ER stress, cell viability, and transcriptomics. The second aim will use Perturb-Seq, which combines CRISPR screens with single-cell RNA sequencing, to identify genes whose perturbations induce transcriptional signatures of cellular stress states, followed by validation in kidney organoids. Ultimately, these experiments will reveal the genes and pathways that mediate FFA-induced lipotoxic injury in kidney cells. Given the largely unmet need for kidney disease therapies, our study will provide a step towards revealing new targets as well as expanding our knowledge on the fundamental mechanisms underlying kidney disease.