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Principal Investigator: Heather A Himburg
Organization: MEDICAL COLLEGE OF WISCONSIN
Fiscal Year: 2024
Award: $546,000
Funding agency: National Institute of Allergy and Infectious Diseases
SUMMARY
Our laboratory has recently reported sex-differences in morbidity during gastrointestinal acute radiation
syndrome (GI-ARS) with adult male rats having increased susceptibility to GI-ARS than age-matched female
rats. This finding is in line with a growing body of evidence from multiple labs which demonstrate GI radiation
sensitivity and response to candidate GI mitigators is sex dependent. Together, these data emphasize the
need for understanding how biological sex regulates normal tissue response to radiation and the consideration
of sex-based differences in MCM development.
In this application to RFA-AI-23-024 (Sex Differences in Radiation Research), we propose to evaluate whether
sex-differences in the regulation of the enzyme ACE2 may be an underlying driver of the observed sex-
difference in radiation sensitivity. Ace2 is an X-linked gene that may escape X-chromosome inactivation to
provide a “double-dosage” of ACE2 mRNA. Additionally, ACE2 mRNA transcription is known to be regulated
by the female estrogen hormone. We hypothesize elevated ACE2 expression and activity in the GI system of
female rats relative to age-matched males may confer a survival advantage during GI-ARS.
ACE2 enzyme activation promotes production of the peptide Ang(1-7) which mediates downstream signaling
via the GPCR Mas receptor (MasR). Ang(1-7) treatment following myelosuppressive radiation injury has been
shown to accelerate hematopoietic recovery and improves survival during ARS. Consistent with these studies,
our lab demonstrated pharmacologic ACE2 agonism with the small molecule diminazene aceturate (DIZE)
promotes survival in rodent models of GI-ARS, H-ARS and the delayed effects of acute radiation exposure
(DEARE). However, we have recently observed that DIZE-mediated mitigation effects during GI-ARS are
more pronounced in male rats than female rats.
Based on these data, we propose three Aims to comprehensively characterize the connection between
biological sex and ACE2 in the pathogenesis of the GI injury. Aim 1 will evaluate whether agonism of the
ACE2/Ang(1-7)/MasR pathway promotes similar GI protection in male and female rats. Aim 2 will determine if
loss of estrogen via ovariectomy alters ACE2 activation and impacts the established sex-differences in GI-
ARS. Finally, in Aim 3, we will characterize the tissue-specific necessity for ACE2 in the gut using inducible
Cre-loxP mouse models. This work will be conducted using dual approaches of pharmacologic and genetic
loss of function studies in well-validated, in vivo animal models of acute radiation injury.
This work will advance our understanding of the mechanisms which contribute to sex-differences in
radiosensitivity. Additionally, as there are currently no FDA-approved medical countermeasures (MCM) for
GI-ARS, our proposed development of ACE2 agonist DIZE as a MCM for GI-ARS has high translational
relevance.
Terms: <21+ years old><7B4 Antigen><7B4 protein><ACE2><Acceleration><Acute><Acute Radiation Syndrome><Adult><Adult Human><Age><Agonist><Ailmentary System><Alimentary System><Ang I (1-7)><AngII><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Angiotensin II><Angiotensin-Forming Enzyme><Angiotensinogenase><Angiotensins><Animal Model><Animal Models and Related Studies><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><BP reduction><Binding><Biological><Blood Serum><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><CD143 Antigens><CD144 Antigen><Carboxycathepsin><Cell Communication and Signaling><Cell Signaling><Childhood><Citrulline><Common Rat Strains><Data><Development><Differences between sexes><Differs between sexes><Digestive System><Dipeptidyl Peptidase A><Endocrine Gland Secretion><Endothelial Cells><Endothelium><Enterocytes><Enzyme Activation><Enzyme Gene><Enzymes><Estrogens><FDA approved><Female><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><Gastrointestinal Body System><Gastrointestinal Injury><Gastrointestinal Organ System><Gene Transcription><Genes><Genetic><Genetic Transcription><Goals><Gonadal Steroid Hormones><Hematopoietic><Histopathology><Hormones><Imaging Device><Imaging Instrument><Imaging Tool><Intestinal><Intestines><Intracellular Communication and Signaling><Kidney><Kidney Urinary System><Kininase A><Kininase II><Laboratories><Link><Location><Lung><Lung Respiratory System><Lyonization><Mediating><Membrane><Messenger RNA><Mice><Mice Mammals><Modeling><Molecular Interaction><Morbidity><Morbidity - disease rate><Murine><Mus><Normal Tissue><Normal tissue morphology><Oophorectomy><Ovariectomy><Pathogenesis><Pathway interactions><Peptides><Peptidyl-Dipeptidase A><Predisposition><Production><Proteins><RNA Expression><Radiation><Radiation Biology><Radiation Dose><Radiation Dose Unit><Radiation Injuries><Radiation Sensitivity><Radiation Tolerance><Radiation Toxicity><Radiation exposure><Radiobiology><Radiosensitivity><Radiotoxicity><Rat><Rats Mammals><Rattus><Receptor Protein><Recovery><Regulation><Renin><Reporting><Research><Rodent Model><Role><Serum><Severities><Sex Differences><Sex Hormones><Sex Steroid Hormones><Sexual differences><Signal Transduction><Signal Transduction Systems><Signaling><Site><Source><Susceptibility><Therapeutic Estrogen><Therapeutic Hormone><Tissues><Toxic effect><Toxicities><Transcript><Transcription><VE-Cadherin><Vascular Endothelial Cadherin><Vascular Endothelial Cadherin 1><Vasoactive Agonists><Vasoconstrictor Agents><Vasoconstrictor Drugs><Vasoconstrictors><Vasopressor Agents><Work><X Chromosome><X Inactivation><X-Chromosome Inactivation><adulthood><ages><angiotensin I (1-7)><angiotensin converting enzyme 2><angiotensin converting enzyme II><angiotensin-(1-7)><biologic><biological sex><biological signal transduction><blood pressure reduction><bowel><cadherin 5><comparing females and males><comparing women and men><design><designing><developmental><dosage><female gonadectomy><female treatment><females compared to males><females compared with males><females versus males><females vs males><fluorescence imaging><fluorescent imaging><gain of function><gastrointestinal><gastrointestinal system><gonadal steroids><hemopoietic><imaging approach><imaging based approach><improved><in vivo><induced Cre><inducible Cre><intestinal barrier><intestinal epithelium><intestinal mucosal barrier><irradiation><irradiation injury><irradiation response><loss of function><lower BP><lower blood pressure><lowers blood pressure><mRNA><male><medical countermeasure><membrane structure><model of animal><mouse model><murine model><novel><pathway><pediatric><pharmacologic><pulmonary><radiation poisoning><radiation response><radio-sensitivity><radiosensitive><receptor><reduce BP><reduce blood pressure><reduction in BP><reduction in blood pressure><renal><response><response to radiation><secondary end point><secondary endpoint><sex><sex based differences><sex steroid><sex-dependent differences><sex-related differences><sex-specific differences><small molecule><social role><treat females><treat women><treatment among females><treatment among women><treatment in females><treatment in women><vasopressor><villin><women compared to men><women compared with men><women versus men><women vs men><women's treatment>