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Principal Investigator: Connie Krawczyk
Organization: VAN ANDEL RESEARCH INSTITUTE
Fiscal Year: 2024
Award: $249,064
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
Sex and gender contribute to the immune system and how we as humans respond to foreign infections. Males
traditionally have an elevated risk of hospitalizations due to infections from birth to old age. Females, however,
have a more protective immune system, yet have an elevated risk of autoimmunity. Thus, the balance between
fighting infections and limiting immune response is stratified. Animal models have allowed us to largely tease
out the role of sex chromosomes and hormones (such as estrogen/testosterone), but they lend little insight into
the role of human gender on the immune response. Disparities between trans- and cis-gender women are
observed in multiple inflammatory and immune phenotypes, from HIV risk to rheumatological conditions. As
gender is a non-binary spectrum, many precision medicine tools can be applied to tease out individuals’
immune system modulators focused on individual assessments of sex chromosomes, sex hormones, and
environmental factors. To do this, we have compiled a multiple PI team that brings strengths from
epigenetics/epidemiology (Dr. Triche), infectious disease modeling (Dr. Krawczyk), and sex
chromosome/hormone genetics (Dr. Prokop). We highlight in this work how the histone methylation regulator
chromosome pair, KDM5C (chrX) and KDM5D (chrY), results in an immune modulation through genome-wide
epigenetic alteration.
We have developed three complementary aims to build an integrated model of KDM5C/KDM5D influence on
individuals’ immune responses. Aim1) Genetics of KDM5C hematopoiesis conditional knockout alteration at
the cellular resolution of the immune system following a chronic viral infection, allowing us to determine cell
types and global epigenetic alterations regulated by the pathway. Aim2) Precision insights for KDM5C/KDM5D
of ~20,000 human blood samples following various immune challenges and the separation of hormone and sex
chromosome using the four-core genotypes rodent model blood single-cell data generation. Aim3) Integrating
our knowledge to individuals for human variants, gene regulation, environmental modulation, and phenotypic
associations for KDM5C/KDM5D. The combination of the three aims represents a precision medicine
approach, allowing us insights into the cells and pathways impacted by the sex chromosome genes during
infection (Aim1), deconvolution of how hormones and sex chromosomes synergistically contribute to immune
cells (Aim2), defining the broad infections and signatures that modulate the genes (Aim2), and integrating this
knowledge to be applied to any individual in a non-binary approach (Aim3). As gender can never be binned
into groups, with an undefined spectrum of individuals within, we lay forth a novel, innovative way for thinking
about how sex and gender both contribute to immune systems without the need for defining gender but
allowing for individualized assessments.
Terms: <65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><Ab response><Aged 65 and Over><Animal Model><Animal Models and Related Studies><Antibodies><Antibody Formation><Antibody Production><Antigen Presentation><Assay><Atlases><Autoimmune Diseases><Autoimmune Status><Autoimmunity><Bacterial Infections><Bioassay><Biological><Biological Assay><Birth><Blood><Blood Reticuloendothelial System><Blood Sample><Blood erythrocyte><Blood specimen><Body Tissues><Bone Marrow Hypoplasia><CMV><COVID-19><CV-19><Cell Body><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Immune Function><Cellular Physiology><Cellular Process><Cessation of life><Chromosomal Synapsis><Chromosome Mapping><Chromosome Pairing><Chronic><Communicable Diseases><Compensation><Coronavirus Infectious Disease 2019><Cytomegalovirus><Data><Data Analyses><Data Analysis><Data Set><Death><Differences between sexes><Differentiation in cell culture><Differs between sexes><Disparities><Disparity><Endocrine Gland Secretion><Environment><Environmental Factor><Environmental Risk Factor><Epidemiology><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Equilibrium><Erythrocytes><Erythrocytic><Estrogens><Exposure to><Female><Four Core Genotypes><Gender><Gender Identity><Gender Role><Gene Action Regulation><Gene Expression Regulation><Gene Localization><Gene Mapping><Gene Mapping Genetics><Gene Regulation><Gene Regulation Process><Gene variant><Generations><Genes><Genetic><Genetic Determinism><Genetic Diversity><Genetic Models><Genetic Variation><Genomics><Gonadal Steroid Hormones><Gonosomes><HCMV><HIV risk><Hematopoiesis><Hematopoietic><Hematopoietic Cellular Control Mechanisms><Histones><Hormonal><Hormones><Hospital Admission><Hospitalization><Human><Human Genetics><Hypocellular Bone Marrow><IFN><Immune><Immune response><Immune system><Immunes><Immunity><Immunological response><Immunomodulation><In vitro cell differentiation><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammatory><Innate Immunity><Interferons><Investments><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Knowledge><Lead><Link><Linkage Mapping><Lupus><M tuberculosis infection><M. tb infection><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MTB infection><Marrow erythrocyte><Mediator><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Genetics><Murine><Mus><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Null Mouse><Parturition><Pathway interactions><Pb element><Phenotype><Population><Production><QTL><Quantitative Trait Loci><RSV infection><Red Blood Cells><Red Cell><Regulation><Research Resources><Resolution><Resources><Respiratory Syncytial Virus Infections><Risk><Rodent><Rodent Model><Rodentia><Rodents Mammals><Role><Salivary Gland Viruses><Scleroderma><Sex Chromosomes><Sex Differences><Sex Hormones><Sex Roles><Sex Steroid Hormones><Sexual differences><Shapes><Sicca Syndrome><Sjogren's Syndrome><Sjogrens><Sjögren Syndrome><Societies><Subcellular Process><Synapsis><T-Cells><T-Lymphocyte><TB infection><TOPMed><Testing><Testosterone><Therapeutic Estrogen><Therapeutic Hormone><Therapeutic Testosterone><Thinking><Tissues><Total Human and Non-Human Gene Mapping><Trans-Omics for Precision Medicine><Trans-Testosterone><Transcript><Tuberculosis><Vaccination><Validation><Variant><Variation><Viral><Viral Diseases><Virus Diseases><Work><above age 65><adaptive immunity><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age of 65 years onward><aged 65 and greater><aged 65+><aged ≥65><allele variant><allelic variant><antibody biosynthesis><autoimmune condition><autoimmune disorder><autoimmune thyroid disease><autoimmune thyroid disorder><autoimmunity disease><bacteria infection><bacterial disease><balance><balance function><biobank><biologic><biological sex><biorepository><blood cell formation><blood corpuscles><cell type><chromosomal sex><chronic infection><cis-female><cis-gender woman><cis-woman><cisgender woman><comparing females and males><comparing women and men><conditional knock-out><conditional knockout><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cost><cytomegalovirus group><data integration><data interpretation><dermatosclerosis><differential expression><differentially expressed><differentiation in culture><differentiation in vitro><disseminated TB><disseminated tuberculosis><environmental risk><epidemiologic><epidemiological><epigenetically><females compared to males><females compared with males><females versus males><females vs males><fighting><fitness><gender difference><gender-associated difference><genetic determinant><genetic mapping><genetic sex><genetic variant><genome scale><genome-wide><genomewide><genomic variant><genotypic sex><gonadal steroids><heavy metal Pb><heavy metal lead><hemopoietic><histone methylation><hospitalization rates><host response><human data><human model><human old age (65+)><immune function><immune modulation><immune regulation><immune system response><immunoglobulin biosynthesis><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><in vitro cellular differentiation><infancy><infant infection><infantile><infected infant><infection due to Mycobacterium tuberculosis><infectious disease model><innovate><innovation><innovative><insight><knowledge integration><large scale data><large scale data sets><large scale datasets><mRNA><male><model of animal><model of human><mouse model><murine model><new approaches><nonbinary><novel><novel approaches><novel strategies><novel strategy><old age><outcome prediction><over 65 years><paralog><paralogous gene><pathway><persistent infection><precision medicine><precision-based medicine><proband><protective effect><resolutions><response><sex><sex based differences><sex dimorphism><sex steroid><sex-dependent differences><sex-related differences><sex-specific differences><sexual dimorphism><sexually dimorphic><social role><synergism><thoughts><thymus derived lymphocyte><tool><trans-women><transcriptional differences><transcriptomics><transgender women><transwoman><transwomen><tuberculosis infection><tuberculous spondyloarthropathy><validations><viral infection><virus infection><virus-induced disease><women compared to men><women compared with men><women versus men><women vs men><xerodermosteosis><≥65 years>