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Principal Investigator: Melissa A Cunningham
Organization: MEDICAL UNIVERSITY OF SOUTH CAROLINA
Fiscal Year: 2024
Award: $407,072
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Systemic lupus erythematosus (SLE) is one of many autoimmune diseases that disproportionately affects
females. Although many risk factors for lupus are identified: >170 genes including GPR174, myriad
environmental exposures, and aberrant X chromosome inactivation, none of these sufficiently explain the steep
rise in incidence of ADs at the time of puberty in a female-specific manner. Epidemiology suggests a major role
for sex hormones and their receptors in autoimmune diseases. We previously showed that female lupus-prone
mice, expressing only a short form of estrogen receptor alpha (ERα short), have significantly reduced renal
disease and increased survival. Determining the mechanism of this protective effect, which is estrogen
dependent, is the primary goal of this proposal. Of note, ERα-/- (null) lupus prone mice were not similarly
protected. Combined, our data suggest that the presence of the short form of ERα confers protection, not the
absence of full-length ERα. Others and we demonstrated a critical role for ERα in dendritic cell (DC) development
and endosomal Toll-like receptor (TLR) responsiveness. Interestingly, the ERα expressed in ERα short mice is
similar in structure to an endogenous ERα variant (ERα46) that lacks the same AF-1 domain, and differentially
regulates gene transcription compared to full length ERα. Overexpressing ERα46 in vitro also modulates TLR-
induced responses, relevant to this proposal. In the proposed study, we will further investigate the role of ERα
short variants in modulating TLR7-induced immune responses, and determine whether genomic and/or non-
genomic mechanisms of ERα short variant action are protective. Our overall hypothesis is that increasing
expression of ERα short or ERα46 in immune cells will be anti-inflammatory, and that the ratio of ERα46
to ERα66 is decreased in lupus patients versus healthy controls. We also hypothesize that targeting
immune cells with novel anti-inflammatory selective estrogen receptor modulators (SERMs) that alter ERα
membrane signaling and/or ERα-induced transcription will uncouple estrogen-mediated anti-inflammatory
responses from those impacting reproductive tissues. We will test our hypotheses by accomplishing these
Specific Aims: 1) Overexpress ERα short or treat immune cells with novel SERMs (OBHS, PaPE) that select for
anti-inflammatory properties of ERα and determine the effect on known TLR7-induced inflammatory endpoints,
2) Investigate effects of membrane-only ERα signaling vs. nuclear only ERα expression on TLR7-induced
pathways in mice, and 3) Identify ERα variants in human monocyte-derived dendritic cells (mo-DCs) and B cells
using droplet digital PCR and Iso-Seq technology, to determine whether ERα46 is differentially expressed in
lupus patients vs. controls, potentially explaining a biologic difference in females predisposed to autoimmunity.
These aims will allow us to determine if we can separate ERα's reproductive effects from its potentially modifiable
immune effects as a therapeutic strategy, which if successful, will provide novel approaches to immune
modulation in lupus and other immune mediated diseases, especially those with a significant sex bias.
Terms: <AF 2><AF-1><AF2><Address><Affect><Age><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antigen-Antibody Complex><Antiinflammatory Effect><Autoantibodies><Autoimmune Diseases><Autoimmune Status><Autoimmunity><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Basal Transcription Factor><Basal transcription factor genes><Binding><Binding Site Domain><Biological><Blood Serum><Blood Vessels><Blood monocyte><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><Cell Body><Cell Communication and Signaling><Cell Function><Cell Line><Cell Physiology><Cell Process><Cell Signaling><Cell membrane><CellLine><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chromatin><Cytoplasmic Membrane><DNA Binding><DNA Binding Interaction><DNA bound><Data><Dendritic Cells><Deposit><Deposition><Development><Differential Gene Expression><Disease><Disorder><Disproportionate number of females><Disproportionate number of women><Disproportionately affects females><Disproportionately affects women><Disproportionately impacts females><Disproportionately impacts women><Disproportionately in females><Disproportionately in women><Dose><ERalpha><ERα><ESR1><ESR1 gene><ESRD><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><Endosomes><Environmental Exposure><Epidemiology><Estradiol Receptor alpha><Estradiol Receptor α><Estrogen Receptor 1><Estrogen Receptor alpha><Estrogen Receptor α><Estrogen Receptors><Estrogens><Event><Female><Gender Bias><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><Genomics><Goals><Gonadal Steroid Hormones><Gonosomes><Human><IFGR2><IFNGR2 protein><Immune><Immune Complex><Immune Targeting><Immune response><Immunes><Immunological response><Immunomodulation><In Vitro><Incidence><Inflammation><Inflammatory><Inflammatory Infiltrate><Inflammatory Response><Innate Immune Response><Interferon Gamma Receptor Accessory Factor-1><Interferon Gamma Receptor Beta Chain><Interferon Gamma Receptor-2><Interferon Gamma Transducer-1><Interferon γ Receptor β Chain><Interferon γ Receptor-2><Intracellular Communication and Signaling><Investigation><Isoforms><Kidney><Kidney Diseases><Kidney Urinary System><Length><Ligand Binding Domain><Location><Lupus><Lupus Erythematosus Disseminatus><Lupus Glomerulonephritis><Lupus Nephritis><Lyonization><Macrophage><Marrow monocyte><Mediating><Membrane><Mice><Mice Mammals><Modern Man><Molecular Interaction><Murine><Mus><Mutant Strains Mice><Mφ><NR3A1><Nephritis><Nephropathy><Nuclear><PBMC><Pathway interactions><Patients><Peripheral Blood Mononuclear Cell><Plasma Membrane><Predisposition><Property><Protein Isoforms><Proteins><Proteinuria><RNA Expression><Race><Races><Receptor Protein><Receptosomes><Renal Disease><Reporting><Research><Risk Factors><Role><SERMs><SLE><Sampling><Selective Estrogen Receptor Modulators><Serum><Sex Bias><Sex Chromosomes><Sex Hormones><Sex Steroid Hormones><Signal Transduction><Signal Transduction Systems><Signaling><Strains Cell Lines><Structure><Subcellular Process><Susceptibility><Systemic Lupus Erythematosus><Systemic Lupus Erythematous><Systemic Lupus Erythmatosus><TLR protein><TLR7><TLR7 gene><Technology><Testing><Therapeutic><Therapeutic Estrogen><Tissue-Specific Differential Gene Expression><Tissue-Specific Gene Expression><Tissues><Toll-Like Receptor 7><Toll-Like Receptor Family Gene><Toll-like receptors><Transactivation><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Variant><Variation><Veiled Cells><Woman><Work><X Inactivation><X-Chromosome Inactivation><ages><anti-inflammatory effect><autoimmune antibody><autoimmune condition><autoimmune disorder><autoimmunity disease><autoreactive antibody><biologic><biological signal transduction><cell type><co-repressor><corepressor><cultured cell line><developmental><differential expression><differentially expressed><digital><disparities in sex><disseminated lupus erythematosus><epidemiologic><epidemiological><experiment><experimental research><experimental study><experiments><female bias><female preponderance><gene co-repressor><gene corepressor><genetic co-repressor><genetic corepressor><gonadal steroids><host response><immune modulation><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><in vivo><kidney disorder><lupus prone mice><male><membrane structure><monocyte><mouse mutant><mutant><new approaches><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation><next generation therapeutics><non-genomic><nongenomic><novel><novel approaches><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><overexpress><overexpression><pathway><plasmalemma><protective effect><prototype><pubertal timing><racial><racial background><racial origin><receptor><renal><renal disorder><reproductive><response><self reactive antibody><sex><sex disparity><sex steroid><social role><systemic lupus erythematosis><tool><trans-activation><transcription factor><transcriptional differences><vascular><women's preponderance>