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Sex-differences in ACE2 Regulate Normal Tissue Toxicity During Gastrointestinal Acute Radiation Syndrome

Award Number: U01AI183904
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/18/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Sex-differences in ACE2 Regulate Normal Tissue Toxicity During Gastrointestinal Acute Radiation Syndrome - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $535,440 )
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	000	2	5/22/2025	NON-COMPETING CONTINUATION	$535,440
														Subtotal = $535,440

Issue Date FY: 2024 ( Subtotal = $546,000 )
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	000	1	6/18/2024	NEW	$546,000
														Subtotal = $546,000

Grand Total All Awards = $1,081,440

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Sex-differences in ACE2 Regulate Normal Tissue Toxicity During Gastrointestinal Acute Radiation Syndrome

Award Number: U01AI183904

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/18/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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