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Principal Investigator: Timothy Brandon Ware
Organization: SCRIPPS RESEARCH INSTITUTE, THE
Fiscal Year: 2024
Award: $76,756
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary/Abstract
The goal of this proposal is to understand how transmembrane protein 164 (TMEM164) attenuates
polyunsaturated fatty acid (PUFA) metabolism and ferroptotic signaling. Ferroptosis is a novel iron-dependent
form of cell death implicated in a broad range of human diseases, including cancer and type 2 diabetes mellitus
(T2DM). In T2DM, the severity of diabetic state increases risk for renal tubular injury related to iron overload and
lipid peroxidation, two key features of ferroptosis. Characterizing enzymes that regulate the PUFA content of
human cells would not only deepen our understanding of ferroptosis, but also identify therapeutic targets for
treating diseases like T2DM where this form of cell death is dysregulated. Recent genome editing screens have
identified TMEM164, a multi-pass transmembrane protein of uncharacterized function, as a key regulator of
ferroptosis. We hypothesize, based on its Alphafold-predicted structure, that TMEM164 is a novel type of
cysteine-dependent transmembrane enzyme that regulates cellular PUFA content. Here we seek to test this
hypothesis and identify the specific enzymatic functions performed by TMEM164 in PUFA lipid metabolism, as
well as their contribution to conferring ferroptosis sensitivity to human cells. In Aim 1, I will determine the lipid
profiles of cells genetically deleted for TMEM164 and test whether wild type, but not a putative catalytic cysteine
mutant form of TMEM164 can rescue these lipid perturbations. From these data, I will define candidate
physiological substrates for TMEM164, which will be tested in recombinant protein systems. In Aim 2, I will
leverage our lab’s longstanding expertise in covalent inhibitor discovery to identify electrophilic compounds that
block TMEM164 activity through modifying the putative catalytic cysteine of the protein. Successful completion
of this project will broaden our fundamental understanding of the lipid metabolic pathways involved in ferroptosis
and identify new candidate drug targets for suppressing the contribution of ferroptosis to human degenerative
diseases like T2DM.
Terms: <Acid-Thiol Ligases><Acyl CoA Synthetases><Acyl Coenzyme A Synthetases><Acyltransferase><Adult-Onset Diabetes Mellitus><Apoptosis><Apoptosis Pathway><Assay><Attenuated><Autoregulation><Bioassay><Biochemistry><Biological Assay><Biological Chemistry><Cancer Model><CancerModel><Cancers><Cell Body><Cell Communication and Signaling><Cell Death><Cell Death Induction><Cell Signaling><Cell membrane><Cells><Cellular biology><Cessation of life><Chemicals><Chemoresistance><Co A Ligases><Coenzyme A Ligases><Coenzyme A Synthetases><Collaborations><Coupled><Cysteine><Cytoplasmic Membrane><Data><Death><Degenerative Disorder><Diabetes Mellitus><Diabetic Kidney Disease><Diabetic Nephropathy><Disease><Disorder><Drug Targeting><EC 2.3><Endothelium><Enzyme Gene><Enzymes><Esters><Ethers><Family><Family member><Fatty Acid Hydroperoxides><Fatty Acid Metabolism Pathway><Fatty Acids><Fe element><Fe overload><Funding><Genes><Genetic><Goals><Grawitz Tumor><Half-Cystine><Homeostasis><Human><Hyperglycemia><Hypernephroid Carcinoma><Hypernephroma><Injury><Integral Membrane Protein><Intracellular Communication and Signaling><Intrinsic Membrane Protein><Investigators><Iron><Iron Overload><Ketosis-Resistant Diabetes Mellitus><Kidney><Kidney Urinary System><L-Cysteine><L-Threonine><Libraries><Link><Lipid Hydroperoxide><Lipid Peroxidation><Lipid Peroxides><Lipids><Lipoperoxides><Lysolecithins><Lysophosphatidylcholines><Malignant Neoplasms><Malignant Tumor><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Maturity-Onset Diabetes Mellitus><Mediating><Medicinal Chemistry><Membrane><Metabolic><Metabolic Pathway><Methods><Modern Man><NIDDM><Nephroid Carcinoma><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Orphan><Ortholog><Orthologous Gene><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Phosphatides><Phospholipid Metabolism><Phospholipids><Physiologic><Physiological><Physiological Homeostasis><Plasma Membrane><Play><Polyunsaturated Fatty Acids><Predisposition><Principal Investigator><Production><Programmed Cell Death><Proteins><Proteomics><Recombinant Proteins><Recombinants><Renal Adenocarcinoma><Renal Cell><Renal Cell Adenocarcinoma><Renal Cell Cancer><Renal Cell Carcinoma><Renal Vascular><Renal vessels><Research Personnel><Researchers><Risk><Role><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Structure><Susceptibility><System><T2 DM><T2D><T2DM><Testing><Threonine><Training><Transmembrane Protein><Transmembrane Protein Gene><Tubular><Tubular formation><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Variant><Variation><adult onset diabetes><attenuate><attenuates><attenuation><biological signal transduction><cell biology><chemoresistant><chemotherapy resistance><chemotherapy resistant><degenerative condition><degenerative disease><desensitization><diabetes><diabetic><drug candidate><experience><fat metabolism><fatty acid metabolism><genome editing><genomic editing><glutathione peroxidase><human disease><hydroxy fatty acid><hyperglycemic><inhibitor><injuries><ketosis resistant diabetes><kidney adenocarcinoma><kidney cell><kidney vascular><kidney vascular structure><lipid metabolism><lipid peroxide><lipidomics><malignancy><maturity onset diabetes><membrane structure><mutant><necrocytosis><neoplasm/cancer><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><oxidation><pharmacologic><plasmalemma><premature><prematurity><renal><renovascular><small molecule><social role><therapeutic target><thiokinase><type 2 DM><type II DM><type two diabetes>