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Spatial metabolomics with subcellular resolution to identify therapeutic targets

具有亚细胞分辨率的空间代谢组学以确定治疗靶点

基本信息

批准号：
10714487
负责人：
Manas Ranjan Gartia
金额：
$ 37.5万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-07 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714487
关键词：
Cardiovascular Diseases Cell Culture Techniques Cell Death Cell Line Cells Chemicals Chemistry Diabetes Mellitus Disease Disease Progression Drug Sensitization Drug resistance Goals Heterogeneity Image In Vitro Iron Lipid Peroxidation Lipids Malignant Neoplasms Maps Methods Modification Molecular Neurodegenerative Disorders Onset of illness Outcome Pathology Pathway interactions Pharmaceutical Preparations Physiological Processes Pre-Eclampsia Raman Spectrum Analysis Recurrent Malignant Neoplasm Resistance Resolution Role Sepsis Techniques Therapeutic Tissues cancer cell cancer recurrence cancer therapy chemotherapy disease phenotype improved in vivo in vivo Model insight iron metabolism lipid metabolism lipidomics liquid chromatography mass spectrometry metabolomics multiple omics novel peroxidation refractory cancer success therapeutic target three dimensional cell culture

项目摘要

Abstract Cell death is a crucial physiological process. The resistance of cancer cells to therapeutic drugs is a significant barrier to successful cancer treatment and the primary factor in cancer recurrence. Activation of novel cell death pathways would resensitize drug-resistant cells to chemotherapy. Ferroptosis is a nonapoptotic cell death activated when the lipid in the cell undergoes iron-dependent peroxidation. Our overarching goal is to investigate lipid metabolism-driven cell death through the modulation of ferroptosis in cell culture and in vivo models of drug- resistant cancer. The results will provide fundamental insights into the molecular chemistry of ferroptosis and its role in disease pathology by developing a multi-omics approach with single-cell resolution. Diseases like cancer, sepsis, pre-eclampsia, diabetes, cardiovascular disease, and neurodegenerative illnesses correlate with lipids and lipid metabolism dysregulation. Lipid distributions are heterogeneous, and their chemical modifications, such as lipid peroxidation, are potentially crucial for disease onset and progression. However, the precise relationship between lipid distribution and their chemical modification and disease pathology is not fully understood. This project investigates changes in lipid distribution and lipid peroxidation both in vitro and in tissues to provide fundamental insights into their molecular chemistry and its role in disease pathology by using the experimental methods developed in our group based on spatial chemical imaging. Our approach uses Raman imaging to provide spatial information about lipids in the defined cellular compartments in contrast to the bulk or fractionated examinations of extracted lipids provided by liquid chromatography-mass spectrometry (LC-MS). This proposal builds upon our prior success in performing spatial imaging of lipid distribution in cells and tissues. The hypotheses underlying this effort are that (a) there are significant heterogeneities in lipid distributions and their chemical modifications, and (b) these heterogeneities can be correlated to the pathology of the disease. In particular, we will: 1) Investigate the effect of ferroptosis on the lipid metabolism and iron metabolism of drug- resistant cell lines in 2D culture; 2) Perform spatial mapping and profiling of lipids during ferroptosis in 3D cell culture; 3) Detect ferroptosis and identify its associated mechanism in vivo. The project outcomes will improve our understanding of the molecular mechanism, disease phenotype, and disease progression leading to better therapeutic strategies.

摘要