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Principal Investigator: Umesh C Sharma
Organization: STATE UNIVERSITY OF NEW YORK AT BUFFALO
Fiscal Year: 2024
Award: $398,750
Funding agency: National Heart Lung and Blood Institute
Immunomodulation of Galectin-3 to Prevent Radiation-Induced Myocardial Fibrogenesis
This application addresses the scientific goals of FOA-PA-19-112. More than half of life-threatening
thoracic cancers are treated with repeated doses of ionizing radiation. Unfortunately, the pro-inflammatory and
pro-fibrotic properties of ionizing radiation increase the cumulative risk of cardiac damage. Galectin-3 (gal3) is a
unique carbohydrate and peptide-binding molecule widely implicated in myocardial inflammation and fibrosis.
Increased myocardial gal3 expression is reported in models of cardiac irradiation, but it is unclear whether gal3
directly contributes to radiation-induced cardiac fibrosis. We aim to determine the function of gal3 in mediating
the inflammatory and fibrotic effects of radiation. We propose to test the hypothesis that gal3 mediates
radiation-induced myocardial inflammation and fibrosis, and that genetic or immunological modulation
of gal3 expression or function neutralizes these effects and is thus cardioprotective. The unique features
of this hypothesis are the concept that radiation exposure activates cardiomyocytes and macrophages to release
gal3, which then binds to high-affinity mast cell surface receptors inducing the release of inflammatory and fibrotic
mediators. Moreover, we have designed a new gal3 immunomodulatory vaccine that neutralizes gal3 after
single-dose intramuscular administration in a mouse model. To test the general hypothesis, we propose three
specific aims.
In Aim I, we will determine the effects of gal3 modulation on inflammation, fibrosis, and cardiac function
after repeated exposure to thoracic radiation. We will use genetically engineered cardiomyocyte-selective gal3
gain-of-function mice to study gal3-myocyte-fibroblast pathways, and bone marrow transplanted mice to study
gal3-macrophage-fibroblast pathways. In Aim II, we will determine the contribution of gal3 released by
cardiomyocytes and macrophages to activate mast cells after in vitro irradiation, as well as the downstream
effects on cardiac fibroblast growth and collagen synthesis using a state-of-the art microchamber system. In Aim
III, we will compare the preventive and therapeutic effects of a new gal3-immunomodulatory vaccine on radiation-
induced cardiac fibrogenesis and dysfunction. The feasibility of this project is confirmed by the a) availability of
gal3 knockout mice for gal3 loss-of-function studies, b) cardio-selective and global gal3 overexpression mice
for cardiac and systemic gain-of-function studies, and c) Myeloablated mice engrafted with gal3-null or gal3-
overexpressing progenitor cells for macrophage-targeted gal3 loss-and gain-of-function studies. A safe and
highly potent gal3 inhibitor vaccine has been designed in our laboratory to study the therapeutic potential of gal3
inhibition. Expected project outcomes include the evidence that gal3 mediates cardiac fibrosis and dysfunction
after cumulative radiation exposure, and pre-clinical data on the protective effects of early gal3
immunomodulation. These studies have important therapeutic implications for timely and targeted interventions
in cancer patients susceptible to radiotherapy-induced myocardial fibrogenesis and loss of cardiac function.
Terms: <Acceleration><Address><Affinity><Algorithms><Attenuated><Binding><Biological Markers><Blood><Blood Reticuloendothelial System><Body Tissues><Bone Marrow Grafting><Bone Marrow Purging><Bone Marrow Transplant><Bone Marrow Transplantation><C-jun Amino-Terminal Kinase><C-jun Kinase-1><C-jun N-Terminal Kinase 1><CBP-30><CBP-35><CBP35><CCND1 Protein><Cancer Patient><Carbohydrate-Binding Protein 35><Carbohydrates><Cardiac><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac Toxicity><Cardiocyte><Cardiotoxic><Cardiotoxicity><Cell Body><Cell Communication><Cell Interaction><Cell Surface Receptors><Cell-to-Cell Interaction><Cells><Cessation of life><Chest><Clinical Research><Clinical Study><Collagen><Cyclin D1><Data><Death><Development><Dose><Dysfunction><Early identification><Engraftment><Epsilon-Binding Protein><Experimental Designs><Exposure to><Fibroblasts><Fibrosis><Fibrosis in the heart><Fibrosis in the myocardium><Fibrosis within the heart><Fibrosis within the myocardium><Fibrotic myocardium><Food and Drug Administration><Functional disorder><G1/S-Specific Cyclin D1><Galectin 3><Generalized Growth><Genes><Genetic><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Goals><Growth><HL-29><Half-Life><Heart><Heart Muscle Cells><Heart failure><Heart myocyte><IgE Binding Protein><IgEBP><Immunization><Immunomodulation><Immunomodulators><In Vitro><Inflammation><Inflammatory><Intervention><Intervention Strategies><Intramuscular><Ionizing Electromagnetic Radiation><Ionizing radiation><JN Kinase><JNK><JNK Mitogen-Activated Protein Kinases><JNK1><JNK1 Kinase><JNK1 protein><JNK1A2><JNK21B1/2><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><L-29 Lectin><L-31><L-34><L30 Lectin><LGALS3><Laboratories><Lung Tissue Fibrosis><MAP Kinase 8><MAP Kinase 8 Gene><MAPK8><MAPK8 Mitogen-Activated Protein Kinase><MAPK8 gene><Mac-2 Antigen><Macrophage><Macrophage-2 Antigen><Malignant Thoracic Neoplasm><Malignant Thoracic Tumor><Malignant Tumor of the Thorax><Malignant neoplasm of thorax><Marrow Mast Cell><Marrow Transplantation><Measures><Mediating><Mediator><Mice><Mice Mammals><Mitogen-Activated Protein Kinase 8><Modeling><Molecular Interaction><Murine><Mus><Muscle Cells><Myocardial><Myocardial depression><Myocardial dysfunction><Myocarditis><Myocardium><Myocytes><Mφ><Null Mouse><Outcome><PRAD1 Protein><PRKM8><Pathway interactions><Patients><Peptides><Physiopathology><Predisposition><Preventive><Process><Progenitor Cells><Proliferating><Property><Proto-Oncogene Proteins c-bcl-1><Publishing><Pulmonary Fibrosis><Radiation><Radiation exposure><Radiation therapy><Radiation-Ionizing Total><Radiotherapeutics><Radiotherapy><Receptor Protein><Recombinant DNA Technology><Recombinant Proteins><Reporting><Risk><SAP Kinase-1><SAPK/JNK><SAPK1 Mitogen-Activated Protein Kinase><SAPK1/JNK><Stress-Activated Protein Kinase JNK1><Stress-Activated Protein Kinase gamma><Surface><Susceptibility><System><Testing><Therapeutic><Therapeutic Agents><Therapeutic Effect><Therapeutic Studies><Therapy Research><Thorace><Thoracic><Thorax><Tissue Basophils><Tissue Growth><Tissues><Transforming Growth Factors><Transgenic Organisms><Tumor Growth Factors><USFDA><United States Food and Drug Administration><Vaccine Adjuvant><Vaccines><Work><attenuate><attenuates><bcl-1 Proto-Oncogene Products><bcl-1 Proto-Oncogene Proteins><bcl1 Proto-Oncogene Proteins><bio-markers><biologic marker><biomarker><c-bcl-1 Proteins><c-jun N-Terminal Kinase><cardiac MRI><cardiac damage><cardiac dysfunction><cardiac failure><cardiac fibrosis><cardiac function><cardiac inflammation><cardiac magnetic resonance imaging><cardiac muscle><cardiomyocyte><cardioprotectant><cardioprotection><cardioprotective><coronary fibrosis><cyclin D><design><designing><developmental><efficacy testing><fibrogenesis><fibrosis in the lung><fibrotic heart><function of the heart><gain of function><genetically engineered><heart damage><heart dysfunction><heart fibrosis><heart function><heart muscle><immune modulation><immune modulators><immune regulation><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><inhibiting antibody><inhibitor><interventional strategy><ionizing output><irradiation><jun-NH2-Terminal Kinase><loss of function><lung fibrosis><mast cell><mastocyte><mouse model><murine model><myeloablation><myocardial fibrosis><neutralizing vaccine><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><new vaccines><next generation therapeutics><next generation vaccines><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><novel vaccines><ontogeny><overexpress><overexpression><paracrine><pathophysiology><pathway><pre-clinical><pre-clinical study><preclinical><preclinical study><prevent><preventing><protective effect><radiation effect><radiation treatment><receptor><response><stem cells><stress-activated protein kinase 1><thoracic cancer><thoracic malignancies><transforming growth factors Animal growth regulators><transgenic><treatment with radiation>