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Principal Investigator: Mu A
Organization: DANA-FARBER CANCER INST
Fiscal Year: 2024
Award: $56,728
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY:
Exercise benefits the body in many ways. The functions of skeletal muscle, brain, liver, bone, adipose tissue
and heart all gain from various types of physical activity and training. People suffering from disabilities, morbid
obesity, or age-related diseases, are usually physically inactive, which exacerbates their symptoms and leads to
development of other types of diseases, such as type 2 diabetes mellitus, cardiovascular diseases, and some
forms of cancers. Scientific explorations of exercise have become more molecular, focusing on the pathways
and molecules that mediate these benefits. Irisin has been identified as an exercise-induced hormone that
embodies many adaptations to exercise in a variety of tissues/organs, including “browning” of subcutaneous
adipose tissue, bone remodeling, improving cognitive deficits and neuropathology, and promoting myogenesis
of skeletal muscles.
In bone and fat, the effects of irisin are mediated via αv integrins, with αvβ5 identified as the major receptor.
However, my biochemical and biophysical characterization of direct interaction between irisin and αvβ5
suggested extremely weak binding, while the concentrations of irisin that induce detectable amount of
irisin-mediated effects in the body and in the cultured cells are really low, indicating a very high irisin/receptor
binding affinity. This paradox could be explained by the existence of an additional factor that facilitates
irisin/integrin interaction and irisin-mediated integrin activation. My preliminary data suggested that an
exercise-induced circulating protein Hsp90α binds to integrin αvβ5, and functions as a cofactor to mediate the
binding of irisin to integrin and irisin-induced integrin signaling. Irisin is different from many integrin ligands in
that irisin is small, heavily glycosylated, and lacks the well-identified integrin binding motif, indicating a
non-canonical ways of ligand binding to integrins.
Biophysical and biochemical approaches will be used to characterize the complexes formed by irisin (WT and
glycosylation mutants), αvβ5 and Hsp90α. The molecular model will be firstly tested in HEK293T cells
ectopically expressing αv and β5, and muscle and fat cells, using molecular approaches and fluorescence
microscopy. The effects of Hsp90α will be further evaluated in mice. Taken together, these studies will advance
our understanding of irisin-mediated (or hormone-mediated, in general) integrin signaling, which will assist drug
and antibody development to treat patients with obesity, aged-related diseases and neuro- or muscular
degenerative disorders.
The proposed project represents a great balance between biochemistry/biophysics as well as cell biology, in
which I was trained during my Ph.D, and cell metabolism and animal physiology, which are the primary
technologies employed by the Spiegelman lab. The resources provided by Bruce’s networks, DFCI and HMS,
tremendously facilitated my research, and will support me to become an independent scientist.
Terms: <Adipocytes><Adipose Cell><Adipose tissue><Adult-Onset Diabetes Mellitus><Affect><Affinity><Affinity Chromatography><Amino Acids><Animals><Antibodies><Arg-Gly-Asp><Arginine-Glycine-Aspartic Acid Cell Adhesion Domain><Binding><Biochemical><Biochemistry><Biological><Biological Chemistry><Biophysics><Blood><Blood Plasma><Blood Reticuloendothelial System><Body Tissues><Bone remodeling><Brain><Brain Nervous System><Bypass><CD51 Antigens><Cancers><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Signaling><Cell surface><Cells><Cellular Metabolic Process><Cellular biology><Cognitive deficits><Cold-Insoluble Globulins><Complex><Cultured Cells><Data><Degenerative Disorder><Development><Disease><Disease Progression><Disorder><Drugs><Dysfunction><Encephalon><Endocrine Gland Secretion><Equilibrium><Exercise><Exhibits><FN1><Fat Cells><Fats><Fatty Tissue><Fatty acid glycerol esters><Fibronectin 1><Fibronectins><Fluorescence Light Microscopy><Fluorescence Microscopy><Functional disorder><Half-Life><Heart><Heart Vascular><Heat Shock><Heat-Shock Reaction><Heat-Shock Response><Hormones><Human><Individual><Integrin Binding><Integrin alphaV><Integrin αV><Integrins><Integrins Extracellular Matrix><Intermediary Metabolism><Intracellular Communication and Signaling><Islam><Ketosis-Resistant Diabetes Mellitus><LETS Proteins><Large External Transformation-Sensitive Protein><Life Style><Lifestyle><Ligand Binding><Ligands><Lipocytes><Liver><Malignant Neoplasms><Malignant Tumor><Mammalian Cell><Maps><Mature Lipocyte><Mature fat cell><Maturity-Onset Diabetes Mellitus><Measures><Mediating><Medication><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Mental disorders><Mental health disorders><Metabolic Diseases><Metabolic Disorder><Metabolic Glycosylation><Metabolic Processes><Metabolism><Mice><Mice Mammals><Modern Man><Mohammedanism><Molecular><Molecular Interaction><Molecular Modeling Nucleic Acid Biochemistry><Molecular Modeling Protein/Amino Acid Biochemistry><Molecular Models><Morbid Obesity><Murine><Mus><Muscle><Muscle Cells><Muscle Fibers><Muscle Tissue><Muslim religion><Myocytes><Myotubes><N-terminal><NH2-terminal><NIDDM><Nature><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nuclear><Opsonic Glycoprotein><Opsonic alpha(2)SB Glycoprotein><Organ><PPAR gamma><PPAR-g><PPAR-γ><PPARgamma><PPARγ><Pathogenesis><Pathway interactions><Pattern><Peroxisome Proliferative Activated Receptor Gamma><Peroxisome Proliferator-Activated Receptor gamma><Peroxisome Proliferator-Activated Receptor γ><Persons><Pharmaceutical Preparations><Physical activity><Physiology><Physiopathology><Plasma><Plasma Serum><Proteins><Psychiatric Disease><Psychiatric Disorder><Publishing><RGD (sequence)><RGD Cell Adhesion Domain><RGD Domain><RGD Motif><RGD Tripeptide Sequence><RGD peptide><RGD tripeptide><Receptor Protein><Recombinant Proteins><Recombinants><Research><Research Resources><Resources><Reticuloendothelial System, Serum, Plasma><Rhabdomyocyte><Role><Scientist><Sedentary behavior><Sedentary life-style><Severe obesity><Signal Transduction><Signal Transduction Systems><Signaling><Site><Skeletal Fiber><Skeletal Muscle><Skeletal Muscle Cell><Skeletal Muscle Fiber><Skeletal Myocytes><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Structure><Surface Proteins><Symptoms><T2 DM><T2D><T2DM><Technology><Testing><Therapeutic><Therapeutic Hormone><Thesaurismosis><Thiazolidinedione Receptor><Tissues><Training><Transcription Activator><Transcription Coactivator><Transcription Factor Coactivator><Transcriptional Activator><Transcriptional Activator/Coactivator><Transcriptional Coactivator><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Voluntary Muscle><Work><adipose><adult onset diabetes><affinity purification><age associated disease><age associated disorder><age associated impairment><age dependent disease><age dependent disorder><age dependent impairment><age related human disease><age-related disease><age-related disorder><age-related impairment><alpha 2-Surface Binding Glycoprotein><alpha(V) Integrin><aminoacid><arginyl-glycyl-aspartic acid><balance><balance function><biologic><biological signal transduction><biophysical characteristics><biophysical characterization><biophysical foundation><biophysical measurement><biophysical parameters><biophysical principles><biophysical properties><biophysical sciences><bone><bone remodelling><cardiovascular disorder><cell biology><cell culture><cell cultures><cell metabolism><cellular metabaolism><circulatory system><cofactor><cognitive defects><degenerative condition><degenerative disease><developmental><disability><drug/agent><endurance exercise><extreme obesity><glycosylation><hepatic body system><hepatic organ system><improved><in vivo><integrin bound><ketosis resistant diabetes><lack of physical activity><malignancy><maturity onset diabetes><mental illness><metabolism disorder><molecular modeling><muscular><mutant><myogenesis><neoplasm/cancer><neuropathologic><neuropathological><neuropathology><novel><obese patients><pathophysiology><pathway><patients with obesity><physical inactivity><polypeptide><prevent><preventing><protein purification><psychiatric illness><psychological disorder><receptor><receptor binding><receptor bound><sedentary><sedentary lifestyle><social role><subcutaneous><subdermal><transcription co-activator><transcriptional co-activator><type 2 DM><type II DM><type two diabetes><white adipose tissue><yellow adipose tissue>