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Principal Investigator: Pedro Antonio Latorre Muro
Organization: DANA-FARBER CANCER INST
Fiscal Year: 2024
Award: $90,000
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary/Abstract
Obesity is a pandemic affecting 40% of the population that increases the risk of serious metabolic diseases
including type 2 diabetes and severe forms of SARS-CoV2 infection. Obesity reduces insulin sensitivity and
dysregulates glucose homeostasis sustaining high blood glucose levels and the development of type 2 diabetes.
Activation of brown adipocytes (BAs) is a promising approach to treat obesity and associated diseases. Brown
adipocytes rely on an extensive network of mitochondria that increases energy expenditure and maintains
glucose homeostasis through glucose, amino acid, and fatty acid oxidation. During fat-induced stress,
mitochondrial-endoplasmic reticulum (ER) communication sustains cellular function in BAs. However, the
mechanisms by which mitochondrial-ER communication shapes cellular adaptation during obesity are poorly
understood. Therefore, studying these pathways will provide new therapeutical approaches to target obesity.
The main goal of this application is to study the mechanisms of mitochondrial-ER communication that ensure
mitochondrial function and cellular homeostasis during diet-induced stress. We have described that in BAs
mitochondrial-ER communication promotes thermogenesis during cold stimulation through the ER-resident
kinase PERK. To follow up this work, in Aim 1, the effects of long-term high fat diet (HFD) will be studied in
UCP1-Cre PERK-/- mice exposed to different dietary and bioenergetic conditions. Our preliminary information
suggests that PERK may be signaling to the chaperone PPID to control mitochondrial protein import. In Aim 2,
structural approaches using Cryogenic Electron Microscopy (CryoEM) will be used to explore the molecular
interactions that control and maintain mitochondrial functions in BAs including mitochondrial protein import,
focusing on PPID-dependent pathway, and cellular respiration during dietary and thermal stress. Finally, in Aim
3 the role of PPID in physiology and cellular functions will be studied in mice exposed to diet and thermal stress.
While Aims 1 and part of 2 will be completed during the training stage, part of Aim 2 and the entire Aim 3 will be
conducted during the independent phase of the award.
The extensive training in different fields proposed in this application including physiology and cellular and
structural biology will provide the tools to become an independent researcher and study the mechanisms of inter-
organalle communication that regulate mitochondrial biogenesis and cellular metabolism. This training will be
received in the vibrant scientific communities of Dana-Farber Cancer Institute and Harvard Medical School. This
environment will expose me to the collaborations and discussions necessary for career development and future
opportunities. Dr. Puigserver mentorship will be supportive to establish those connections and actively guide me
in talk and manuscript preparation, student mentorship, experimental design, and career development. Together,
the research and career development plans proposed in this application will strengthen my skills and
competitiveness to become an independent researcher at a major institution.
Terms: <70-kD Heat-Shock Protein><Active Follow-up><Adipocytes><Adipose Cell><Adipose tissue><Adrenergic Agents><Adrenergic Drugs><Adrenergic Receptor><Adrenergics><Adrenoceptors><Adult-Onset Diabetes Mellitus><Affect><Amino Acids><Ampullary Crest><Autoregulation><Award><Binding><Biochemical><Bioenergetics><Biogenesis><Blood Glucose><Blood Sugar><Body Weight><COVID-19 infection><COVID-19 virus infection><COVID19 infection><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cancers><Cardiovascular Diseases><Cas nuclease technology><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Respiration><Cell Signaling><Cellular Function><Cellular Physiology><Cellular Process><Cellular Respiration><Cellular biology><Chaperone><Client><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Collaborations><Communication><Communities><Complex><Country><Crista ampullaris><Cryo-electron Microscopy><Cryoelectron Microscopy><D-Glucose><DF/HCC><Dana-Farber Cancer Institute><Data><Development><Development Plans><Development and Research><Dextrose><Diabetes Mellitus><Diet><Disease><Disorder><Electron Cryomicroscopy><Endoplasmic Reticulum><Energy Expenditure><Energy Metabolism><Ensure><Environment><Epidemic><Epinephrine Receptors><Equilibrium><Ergastoplasm><Event><Exercise><Experimental Designs><Exposure to><Fat Cells><Fats><Fatty Acids><Fatty Liver><Fatty Tissue><Fatty acid glycerol esters><Future><Glucose><Goals><HSP 70><HSP-90><HSP70><HSP90><Health><Heat Production><Heat-Shock Proteins 70><Heat-Shock Proteins 90><High Fat Diet><Homeostasis><In Vitro><In vivo analysis><Individual><Inflammation><Institution><Insulin Resistance><Intermediary Metabolism><Intracellular Communication and Signaling><Investigators><KO mice><Ketosis-Resistant Diabetes Mellitus><Knock-out Mice><Knockout Mice><Knowledge><Laboratories><Levarterenol><Levonorepinephrine><Lipocytes><Liver><Liver Steatosis><Long-Term Effects><Longterm Effects><LoxP-flanked allele><Malignant Neoplasms><Malignant Tumor><Manuscripts><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mature Lipocyte><Mature fat cell><Maturity-Onset Diabetes Mellitus><Membrane><Mentorship><Metabolic Diseases><Metabolic Disorder><Metabolic Processes><Metabolism><Mice><Mice Mammals><Microscope><Mitochondria><Mitochondrial Proteins><Modeling><Molecular><Molecular Chaperones><Molecular Interaction><Monitor><Murine><Mus><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Noradrenaline><Norepinephrine><Nuclear Proteins><Null Mouse><Obesity><Organ><Organelles><Origin of Life><Outcome><PERK kinase><PRK-like ER kinase><Pathway interactions><Phase><Physiological Homeostasis><Physiology><Population><Preparation><Protein Import><Protein Precursors><R & D><R&D><Receptor Signaling><Regulation><Regulatory Element><Research><Research Personnel><Researchers><Risk><Role><SARS-CoV-2 infection><SARS-CoV2 infection><Sampling><Severe acute respiratory syndrome coronavirus 2 infection><Shapes><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Skeletal Muscle><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Stress><Students><Subcellular Process><T2 DM><T2D><T2DM><Thermogenesis><Thesaurismosis><Training><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Voluntary Muscle><Weight Gain><Weight Increase><Work><acid stress><active followup><adenoreceptor><adipose><adiposity><adult onset diabetes><aerobic metabolism><aerobic respiration><age associated><age associated disease><age associated disorder><age associated impairment><age correlated><age dependent><age dependent disease><age dependent disorder><age dependent impairment><age linked><age related><age related human disease><age specific><age-related disease><age-related disorder><age-related impairment><aminoacid><balance><balance function><biological signal transduction><blood glucose regulation><body weight gain><body weight increase><bone><cardiovascular disorder><career development><cell biology><coronavirus disease 2019 infection><corpulence><crista ampulla><cristae><cryo-EM><cryoEM><cryogenic electron microscopy><developmental><diabetes><diet control><diet-associated obesity><diet-induced obesity><diet-related obesity><dietary><dietary control><diets><energy balance><fatty acid oxidation><floxed><floxed allele><follow up><follow-up><followed up><followup><glucose control><glucose homeostasis><glucose regulation><hepatic body system><hepatic organ system><hepatic steatosis><hepatosteatosis><hsp70 Family><hsp90 Family><improved><in vivo><in vivo evaluation><in vivo testing><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><insulin resistant><insulin sensitivity><insulin tolerance><ketosis resistant diabetes><malignancy><maturity onset diabetes><medical college><medical schools><membrane structure><metabolism disorder><mitochondrial><mouse model><murine model><neoplasm/cancer><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><oxidative metabolism><pandemic><pandemic disease><pathway><perk gene product><preparations><protein complex><protein function><research and development><response><school of medicine><skills><social role><stressor><structural biology><sugar><therapeutic target><thermal stress><thermo stress><tool><type 2 DM><type II DM><type two diabetes><white adipose tissue><wt gain><yellow adipose tissue>