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Role of Testosterone Induction of Hydrogen Sulfide in Erectile Dysfunction

Award Number: R03DK131242
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/12/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Role of Testosterone Induction of Hydrogen Sulfide in Erectile Dysfunction - Project Summary/Abstract Testosterone insufficiency is an adverse health condition that affects an increasing number of men. It may be caused by prostate cancer treatment, but also by conditions associated with poor cardiometabolic health such as obesity, diabetes, and hypertension. Erectile dysfunction (ED) is a common symptom in men with testosterone insufficiency. The proposed research seeks to identify why testosterone has a protective effect on the erectile system. Specifically, the possibility that testosterone activates cystathionine γ-lyase (CSE) will be investigated. CSE is the primary enzyme that produces hydrogen sulfide in the vasculature. Hydrogen sulfide is an important cellular signaling molecule that is known to have antioxidant, anti-inflammatory, and vasodilatory properties. The vasodilatory effects of testosterone will be investigated in genetically modified mice lacking the CSE gene, as well as their unmodified littermate controls. Tissue segments from these animals will also be incubated with varying concentrations of testosterone, after which hydrogen sulfide production capacity will be measured. Tissue segments from the corpus cavernosum and the arteries responsible for supplying blood to the penis will be used for these studies, which include the internal iliac artery and proximal and distal segments of the internal pudendal artery. Previous studies indicate that chronic oxidative stress is a causative factor in ED pathogenesis in response to testosterone insufficiency. One mechanism by which hydrogen sulfide exerts cellular signaling is through binding to protein thiol groups, termed sulfhydration. It is hypothesized that hydrogen sulfide acts in such a manner to promote the nuclear related factor 2 (Nrf2) translocation to the nucleus. Nrf2 is an important transcription factor that regulates transcription of many cytoprotective and antioxidant genes. The ability of hydrogen sulfide to induce antioxidant defense and alleviate erectile dysfunction in a mouse model of testosterone insufficiency will be investigated. Male mice will receive a sham or castration surgery, after which castrated mice will remain untreated, or receive a low-dose or a high-dose of an orally active, slow-releasing hydrogen sulfide donor. Following the intervention, erectile function will be assessed by measuring intracavernous pressure changes in response to electrical stimulation of the cavernous nerve. Neurovascular, endothelial, and smooth muscle function will be assessed in the corpus cavernosum, internal iliac artery, and distal and proximal segments of the internal pudendal artery using an ex vivo myograph system. Expression of cytoprotective and antioxidant genes regulated by Nrf2 will be assessed in these tissues by quantitative RT- PCR. Cytosolic and nuclear content of Nrf2 in these tissues will be measured by cellular fractionation and Western blot. The penile redox state will be examined by measuring in vivo reactive oxygen species using a microdialysis technique.


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 = -$63,899 )
2025	2023	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/28/2025	NON-COMPETING CONTINUATION	-$63,899
														Subtotal = -$63,899

Issue Date FY: 2023 ( Subtotal = $171,107 )
2023	2023	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	1/9/2023	SUPPLEMENT FOR EXPANSION	$61,609
2023	2023	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/6/2023	NON-COMPETING CONTINUATION	$109,498
														Subtotal = $171,107

Issue Date FY: 2022 ( Subtotal = $217,842 )
2022	2022	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	9/13/2022	SUPPLEMENT FOR EXPANSION	$112,659
2022	2022	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/12/2022	NEW	$105,183
														Subtotal = $217,842

Grand Total All Awards = $325,050

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Role of Testosterone Induction of Hydrogen Sulfide in Erectile Dysfunction

Award Number: R03DK131242

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/12/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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