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Principal Investigator: Marta Rodriguez Garcia
Organization: WAYNE STATE UNIVERSITY
Fiscal Year: 2024
Award: $514,523
Funding agency: National Institute on Aging
PROJECT SUMMARY
Urogenital infections, including sexually transmitted infections and other genitourinary tract infections, are a
major source of morbidity and mortality in older women, yet how aging impacts mucosal immune protection in
the female genital tract (FGT) remains largely unknown. Thus, to enable the development of preventive
approaches effective in younger and older women, it is critical to identify the early mucosal mechanisms that
confer protection from infection in the FGT and learn how aging alters these protective mechanisms.
Neutrophils are key cells for first-line innate protection and are involved in responses to genital infections,
including bacterial, fungal, and viral pathogens. Neutrophils are also involved in physiological reproductive
functions and are the first-responder cells to sites of injury to initiate the wound healing process. While the
presence of other immune cell types declines with age in the FGT, neutrophils remain constant. However, despite
neutrophils’ critical role in innate protection and tissue homeostasis, and their continual presence in the FGT with
age, the extent to which aging impacts FGT neutrophil-mediated protection against infection or tissue
inflammation as women age is unknown.
The PI’s research group recently discovered that, despite neutrophil presence in the FGT of older women, their
antiviral responses are compromised. Using novel multi-omics technologies, they have identified different
subsets of neutrophils with defense and homeostatic functions, and defined neutrophil intra-tissue spatial
location and transcriptional profiles in younger women. Building on these preliminary results, the central
hypothesis is that aging modifies tissue distribution and function of specific neutrophil subsets, leading to
decreased neutrophil-mediated mucosal protection and increased tissue inflammation in the FGT as women
age.
Using human hysterectomy samples from endometrium, endocervix, and ectocervix from younger and older
women, this project will combine multi-omics single-cell sequencing approaches, tissue spatial transcriptomics,
and in vitro functional assays of genital neutrophils to define how aging modifies neutrophil defense and
homeostatic functions, tissue distribution, and their contribution to first-line mucosal protection.
It is expected that these studies will define, for the first time, the mechanisms responsible for neutrophil-mediated
protection in the FGT and how they are modified with aging. The identification of an inducible/modifiable form of
innate protection in the FGT and how aging modifies this protection will have a positive translational impact,
enabling the development of novel strategies for protection against sexually-transmitted infections and other
genitourinary tract infections in older women, a group that is generally excluded from STI prevention research.
Terms: <Affect><Age><Aging><Anti-viral Response><Antibodies><Assay><Atrophic><Atrophy><Autoregulation><Bioassay><Biological Assay><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Body Tissues><Candida><Cell Body><Cell Communication><Cell Interaction><Cell-to-Cell Interaction><Cells><Cellular Immune Function><Chlamydia><Communication><Defense Mechanisms><Development><Drug or chemical Tissue Distribution><Early identification><Ectocervix><Endocervix><Endometrium><Environment><Epithelial Cells><Epithelium><Exclusion><Exocervix><Expression Signature><Female Genital Organs><Female genitalia><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Functional impairment><GU Infection><Gene Expression Profile><Genital Organs><Genitalia><Genitourinary System Infection><Genitourinary infection><Gonococcal Infection><Gonorrhea><Homeostasis><Human><Hysterectomy><Immune><Immunes><Impairment><In Vitro><Infection><Infiltration><Inflammation><Injury><Innate Immune Response><Intervention><Intervention Strategies><Knowledge><Leanness><Learning><Ligands><Literature><Location><Marrow Neutrophil><Mediating><Medical><Menses><Menstruation><Miyagawanella><Modern Man><Monilia><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Tissue><Mucous Membrane><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Non-Polyadenylated RNA><Pathology><Pathway interactions><Phenotype><Physiologic><Physiological><Physiological Homeostasis><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Position><Positioning Attribute><Pre-Menopause><Pre-menopausal Period><Premenopausal><Premenopausal Period><Premenopause><Preventative strategy><Prevention Research><Prevention strategy><Preventive><Preventive strategy><Process><RNA><RNA Gene Products><Receptor Protein><Receptor Signaling><Research><Ribonucleic Acid><Role><STD prevention><STI prevention><Sampling><Sexually Transmitted Diseases><Sexually Transmitted Disorder><Sexually Transmitted Infection><Signal Pathway><Single cell seq><Site><Source><Technology><Testing><Therapeutic><Thinness><Time><Tissue Distribution><Tissues><Urinary tract infection><Urinary tract infectious disease><Uterine lining><Venereal Diseases><Venereal Disorders><Venereal Infections><Viral><Woman><Women's mortality><Work><Wound Repair><adaptive immune response><age associated><age associated decline><age correlated><age dependent><age dependent decline><age linked><age related><age related decline><age specific><ages><bacteria pathogen><bacterial pathogen><bedsonia><cell type><death among females><death among women><death in females><death in women><death rate among women><death rate in women><decline with age><developmental><experience><female death><female genital tract><female genital tract infection><female mortality><female reproductive tract><female reproductive tract infection><first responder><flow cytophotometry><fungal pathogen><fungi pathogen><gene expression pattern><gene expression signature><genital infection><genital tract infection in women><genitourinary tract><global gene expression><global transcription profile><high dimensionality><immune function><improved><in vitro Assay><infection in the female genital tract><infection in the female reproductive tract><infectious disease of genitourinary system><injuries><interventional strategy><menstrual period><monthly period><monthly periods><mortality><mortality among females><mortality among women><mortality in females><mortality in women><mouse model><multiomics><multiple omics><murine model><neutrophil><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><older women><panomics><pathogen><pathogenic bacteria><pathogenic fungus><pathogenic virus><pathway><pre-menopausal><premenopausal status><prevent><prevent sexually transmitted disease><prevent sexually transmitted infections><preventing><psychological defense mechanism><receptor><repair><repaired><reproductive><reproductive function><reproductive tract infection in women><response><senescence><senescent><sexually acquired infection><sexually transmitted disease prevention><sexually transmitted infection prevention><single cell next generation sequencing><single cell sequencing><social role><transcriptional profile><transcriptional signature><transcriptome><transcriptomics><translational impact><urinary infection><urogenital infection><urogenital tract><viral pathogen><virus pathogen><women's death><women's death rate><women's genital tract><women's reproductive tract><wound healing><wound recovery><wound resolution><young woman>