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Dissecting the molecular mechanisms underlying lipotoxicity in the kidney.

剖析肾脏脂毒性的分子机制。

基本信息

批准号：
10487481
负责人：
Choah Kim
金额：
$ 2.57万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2023-05-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10487481
关键词：
Affect Biological Blood Circulation CRISPR screen Carbon Cell Death Cell Survival Cellular Stress Cellular Stress Response Characteristics Chronic Kidney Failure Cluster Analysis Complex Data Development Diabetic Nephropathy Dietary Fats Disease Disease Progression Edema Environmental Risk Factor Epithelial Cells Equilibrium Exposure to Filtration Gene Expression Profile Gene Expression Profiling Genes Genetic Glomerular Filtration Rate Goals Homeostasis Human Hyperglycemia Hyperlipidemia In Vitro Incubated Individual Injury Intake Kidney Kidney Diseases Kidney Failure Knowledge Lead Length Lesion Libraries Lipids Measures Mediating Metabolic Diseases Methods Molecular Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obesity Organoids Pathogenesis Pathologic Pathway interactions Patients Play Proteins Proteinuria Renal function Research Risk Factors Role Structure of beta Cell of islet Testing Tissues Tubular formation Urine Validation base cell injury diabetic differential expression endoplasmic reticulum stress experimental study glomerulosclerosis induced pluripotent stem cell insight kidney cell nephrogenesis new therapeutic target response single-cell RNA sequencing stress state therapeutic development transcriptomics

项目摘要

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.

摘要慢性肾脏疾病影响着全世界数百万人。遗传和环境因素的结合会导致肾脏疾病的发展肥胖是2型代谢疾病的危险因素糖尿病（T2 D），与肾脏疾病进展高度相关。2型糖尿病的特征通常是血液中高水平的脂质，这可能对肾脏等非脂肪组织有毒。的随之而来的脂毒性可能会损害肾细胞，导致糖尿病等疾病的发病机制，脂毒性对肾脏的具体细胞影响尚不清楚。第一个目标是确定哪些游离脂肪酸对肾小管上皮细胞具有脂毒性，以及它们诱导的细胞应激反应，读出方法如ER应激、细胞活力和转录组学。第二个目标将使用Perturb-Seq，将CRISPR筛选与单细胞RNA测序相结合，细胞应激状态的转录特征，然后在肾类器官中验证。最终，这些实验将揭示介导FFA诱导的肾细胞脂毒性损伤的基因和途径。给定肾脏疾病治疗的需求在很大程度上未得到满足，我们的研究将为揭示新靶点迈出一步以及扩大我们对肾脏疾病基本机制的认识。