Document text
Principal Investigator: J. Marie Hardwick
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $245,625
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Programmed cell death (self-induced) is intrinsic to cellular life, including unicellular species. However, cell
death research has focused primarily on animal models to understand cancer, degenerative disorders, and
developmental processes. In contrast, there is comparably little knowledge of how prokaryotic and eukaryotic
microbes die, and cell death mechanisms in human fungal pathogens (multi- or unicellular) are nearly
unstudied. Over a million fungal infections are diagnosed annually, many causing significant mortality, and
resistance to conventional therapies continues to increase. Building on the principles of cell death discovered
in the metazoan cell death field, we propose to characterize novel cell death pathways in unicellular fungal
species using the tractable Saccharomyces cerevisiae model system. Targeted genetic approaches, cell
biological and biochemical approaches will be used to dissect a vesicle trafficking cell death pathway in yeast
that results in lysosome/vacuole membrane permeabilization and cell death, with implications for the human
pathogen Cryptococcus neoformans. This new mechanistic understanding is intended to provide fundamental
knowledge needed for the future development of new therapeutic strategies analogous to successes in
targeted cancer therapy by inducing intrinsic cell death mechanisms.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Agriculture><Animal Model><Animal Models and Related Studies><Animals><Apoptosis><Apoptosis Pathway><Bacteria><Baker's Yeast><Biochemical><Biologic Models><Biological><Biological Metamorphosis><Biological Models><Brewer's Yeast><C auris><C neoformans><C. auris><C. neoformans><COVID-19><CV-19><Cancer Treatment><Cancers><Candida auris><Cell Body><Cell Death><Cell Membrane Permeability><Cells><Cessation of life><Collection><Complex><Coronavirus Infectious Disease 2019><Cryptococcus neoformans><Death><Degenerative Disorder><Destinations><Developing fetus><Development><Developmental Process><Diagnosis><Disease><Disorder><Drug resistance><Eukaryota><Eukaryote><Evolution><Fetal Development><Filamentous Fungi><Fungus Diseases><Future><Genes><HIV><Human><Human Immunodeficiency Viruses><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunosuppressed Host><In Vitro><Increase lifespan><Individual><Infection><Inflammatory><Innate Immunity><Knowledge><LAV-HTLV-III><Lead><Life><Lymphadenopathy-Associated Virus><Lysosomes><M tuberculosis infection><M. tb infection><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MTB infection><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mammalia><Mammalian Cell><Mammals><Membrane><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Microbe><Model System><Modeling><Modern Man><Molds><Molecular><Molecular Mechanisms of Action><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Mycoses><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Nutrient><Organism><Pathogenicity><Pathologic><Pathway interactions><Pb element><Permeability><Physiologic><Physiological><Process><Programmed Cell Death><Proteins><Public Health><Reporting><Research><Resistance><Role><S cerevisiae><S. cerevisiae><Saccharomyces cerevisiae><Starvation><Stress><Surface Proteins><TB infection><Testing><Therapeutic Fungicides><Tuberculosis><Tumor Cell><VDAC1><VDAC1 gene><Vacuole><Vesicle><Virulence><Virus><Virus-HIV><Whole Organism><Yeasts><anti-cancer therapy><anti-fungal><anti-fungal agents><anti-fungal drug><biologic><cancer therapy><cancer-directed therapy><candidate identification><cell suicide><cellular suicide><commit suicide><completed suicide><conventional therapy><conventional treatment><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><degenerative condition><degenerative disease><developmental><disseminated TB><disseminated tuberculosis><drug resistant><elongating the lifespan><extend life span><extend lifespan><frontier><fungal infection><fungal pathogen><fungi pathogen><fungus><fungus infection><genetic approach><genetic strategy><genome wide screen><heavy metal Pb><heavy metal lead><human pathogen><immunosuppressed patient><infection due to Mycobacterium tuberculosis><knockout gene><lifespan extension><living system><lysosome membrane><malignancy><membrane permeability><membrane structure><membrane synthesis><metamorphosis><microorganism><model of animal><mortality><mouse model><murine model><necrocytosis><neoplasm/cancer><neoplastic cell><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><offspring><pathogenic fungus><pathway><pore forming protein><porin><prevent><preventing><resistance to Drug><resistant><resistant to Drug><social role><success><suicidal morbidity><suicide death><suicide morbidity><targeted cancer therapy><trafficking><tuberculosis infection><tuberculous spondyloarthropathy>