Document text
Principal Investigator: Yizhi Sun
Organization: DANA-FARBER CANCER INST
Fiscal Year: 2024
Award: $127,781
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Abstract
Thermogenic adipocytes and adaptive thermogenesis are promising therapeutic targets for treating and
preventing obesity and obesity-linked diabetes. We recently demonstrated that the mitochondrial tissue-
nonspecific alkaline phosphatase, TNAP, plays a crucial role in the futile creatine cycle (FCC) and adaptive
thermogenesis by hydrolyzing phosphocreatine. Pharmacological inhibition or genetic ablation of TNAP in mice
reduces systemic energy expenditure. Genetic ablation of TNAP in mice also causes rapid-onset obesity. TNAP
assumes a mitochondrial localization specifically in thermogenic adipocytes, which might ensure the cell-
selectivity of the phosphocreatine hydrolysis events and the FCC operation. Here, we propose to study the
metabolic effects of gain-of- function of TNAP in the adipose tissues in mice, as well as the molecular mechanism
and regulation of its mitochondrial localization. Using a transgenic mouse strain that artificially expresses TNAP
in the adipose tissues, we will investigate its effects on obesity, diabetes, fatty liver, and energy expenditure. To
study the TNAP localization, we will test whether its cell specificity lies in the TNAP polypeptide or its trafficking
pathway, or both. I will first determine whether there are any molecular elements (e.g., PTMs or amino acid
sequences) on the TNAP polypeptide crucial for its mitochondrial localization. This will be done using a
combination of biochemical and cell imaging approaches. In addition, we will investigate the cellular pathway of
TNAP trafficking to mitochondria. We will interrogate the role of lipid rafts in TNAP localization. This might allow
us to identify key regulators and mediators of the mitochondrial localization of TNAP. Finally, we will identify
other mitochondrial proteins that share the localization pathway of TNAP and study their functions.
The candidate, Dr. Yizhi Sun, has a strong track record of innovative research with a focus on the molecular
mechanisms of diseases. The candidate’s career goal is to become an independent academic investigator with
a research laboratory oriented towards understanding and reversing obesity and obesity-linked metabolic
disorders. The proposed research will be conducted in the laboratory of Bruce Spiegelman, PhD at Dana-Farber
Cancer Institute and Harvard Medical School, who is a leader in the fields of molecular metabolism and adipocyte
biology. The proposed studies will also bring together leading laboratories of the advisory committee that have
expertise in cell imaging, protein trafficking, and mitochondrial biology. All of these, together with the ideal
research environment in the Longwood Medical Area, will maximize applicant’s potential to successfully
transition to an independent investigator.
Terms: <Ablation><Abnormal Assessment of Metabolism><Acceleration><Active Oxygen><Address><Adipocytes><Adipose Cell><Adipose tissue><Advisory Committees><Alkaline Phosphatase><Amino Acid Sequence><Animals><Area><Automobile Driving><Binding Proteins><Biochemical><Biological><Biology><Biophysics><Body Tissues><Cancers><Cardiovascular Diseases><Cell Body><Cell Communication and Signaling><Cell Membrane Lipid Rafts><Cell Signaling><Cells><Chemicals><Consumption><Creatine><Creatine Phosphate><Cysteine><DF/HCC><Dana-Farber Cancer Institute><Data><Dephosphorylation><Diabetes Mellitus><Disease><Disorder><Doctor of Philosophy><Elements><Energy Expenditure><Energy Metabolism><Ensure><Environment><Event><FP593><Fat Cells><Fats><Fatty Liver><Fatty Tissue><Fatty acid glycerol esters><Futile Cycling><Futile Cyclings><Futile Substrate Cycling><Futile Substrate Cyclings><Generations><Genes><Genetic><Goals><Half-Cystine><Heat Production><Hydrolysis><Immune Precipitation><Immunoprecipitation><Intermediary Metabolism><Intracellular Communication and Signaling><Investigators><Kidney Diseases><L-Cysteine><Laboratories><Laboratory Research><Ligand Binding Protein><Ligand Binding Protein Gene><Link><Lipocytes><Liver Steatosis><Malignant Neoplasms><Malignant Tumor><Mature Lipocyte><Mature fat cell><Mediator><Medical><Membrane Microdomains><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Processes><Metabolic Studies><Metabolism><Metabolism Studies><Methods><Mice><Mice Mammals><Mitochondria><Mitochondrial Proteins><Molecular><Mouse Strains><Murine><Mus><Muscle Fibers><Mutation Analysis><Myotubes><Nephropathy><Obesity><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Oxygen Radicals><Pathway interactions><Ph.D.><PhD><Phosphocreatine><Phosphorylation><Phosphorylcreatine><Physiologic><Physiological><Play><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Prevention><Primary Protein Structure><Pro-Oxidants><Process><Protein Binding><Protein Dephosphorylation><Protein Modification><Protein Phosphorylation><Protein Trafficking><Proteins><Proteome><Proteomics><Public Health><Reactive Oxygen Species><Regulation><Renal Disease><Reporter><Research><Research Personnel><Researchers><Respiration><Rhabdomyocyte><Role><Signal Transduction><Signal Transduction Systems><Signaling><Skeletal Fiber><Skeletal Muscle Cell><Skeletal Muscle Fiber><Skeletal Myocytes><Specificity><Sphingolipid Microdomains><Sphingolipid-Cholesterol Rafts><Task Forces><Testing><Therapeutic><Thermogenesis><Thesaurismosis><Tissue Engineering><Tissues><Transgenic Mice><Transportation><Travel><Variant><Variation><Visualization><Work><adipocyte biology><adipose><adiposity><advisory team><alkaline phosphomonoesterase><bioengineered tissue><biologic><biological signal transduction><biophysical foundation><biophysical principles><biophysical sciences><bound protein><cardiovascular disorder><career><cell imaging><cellular imaging><corpulence><diabetes><diet-associated obesity><diet-induced obesity><diet-related obesity><drFP583><driving><ds red protein><dsFP593><engineered tissue><gain of function><genetic approach><genetic strategy><glycerophosphatase><hepatic steatosis><hepatosteatosis><imaging approach><imaging based approach><imaging study><innovate><innovation><innovative><kidney disorder><lipid raft><malignancy><medical college><medical schools><metabolic abnormality assessment><metabolism disorder><mitochondrial><neoplasm/cancer><novel><obesity intervention><obesity prevention><obesity therapy><obesity treatment><operation><operations><pathway><pharmacologic><polypeptide><prevent obesity><protein sequence><protein transport><red fluorescent protein><renal disorder><respiratory mechanism><school of medicine><social role><therapeutic target><trafficking><white adipose tissue><yellow adipose tissue>