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Characterizing the role of the heme catabolism in tissue damage and inflammation.

Award Number: R01DK125846
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: 03/29/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Characterizing the role of the heme catabolism in tissue damage and inflammation. - Project Summary Gastrointestinal syndrome (GIS) remains a significant clinical problem with no effective treatment. Radiotherapy and chemotherapy lead to bleeding and cell death resulting in release of hemoglobin and/or free heme. Accumulating data suggest that free heme stimulates the production of reactive oxygen species (ROS) and acts as a pro-inflammatory danger-associated molecular pattern (DAMP) through its binding to Toll-Like Receptor 4 (TLR4). In this study, we will focus on understanding how free heme regulates inflammation through gene regulation in myeloid or epithelial cells in the gut in the GIS models. Our data indicate there are high numbers of infiltrating heme oxygenase-1 (HO-1)-positive macrophages (Mø) in colonic biopsies from patients after radiotherapy versus non-irradiated controls or in the ischemic intestine compared to matched normal tissues. Further, we showed that myeloid cell-specific deletion of HO-1 resulted in abnormal epithelial cell proliferation and increased DNA damage (phosphorylated histone H2AX (H2AXg)) in the intestine upon irradiation. We propose that removal of free heme by the heme scavenger, hemopexin (Hx), and/or by the activity of HO-1 (or biological products) may be potential therapeutic option for patients with GIS. Our new preliminary data showed heightened levels of colonic damage and inflammation in Hx-/- mice in response to phenylhydrazine-induced hemolysis. We also demonstrated that heme affects gene expression through binding to G-quadruplex (G4) secondary structures in genomic DNA, which are key regulators of genomic stability, transcription and replication. Our state-of-the-art experimental approaches will allow us to dissect functions of free heme in myeloid and colonic epithelial cells during treatment-induced inflammation and tissue damage. Moreover, we will assess the impact of the gut microbiota in the protective effects of HO-1/Hx against GIS. Specifically, in this proposal we intend to: 1. Characterize the role of free heme in colonic epithelial and myeloid cells in vitro. 2. Determine the role of myeloid cell-expressed HO-1 and heme-regulated gut microbiota diversity in the GIS models. 3. Assess the therapeutic potential of recombinant Hx in the GIS models. 4. Characterize the staining of HO-1, Hx, DNA damage and proliferation markers and G4 in biopsies from patients with GIS and correlate immunostaining with clinical parameters. In summary, this study will pursue the definition of a novel role and mechanisms by which free heme acts as a key player in regulating gene expression upon tissues injury and gut inflammation such as observed in patients with GIS and/or colitis. This study will not only have high impact on the field of heme biology but will also contribute to developing much needed treatment strategies for GIS patients.


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: 2024 ( Subtotal = $502,661 )
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/19/2024	NON-COMPETING CONTINUATION	$471,245
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/10/2024	NON-COMPETING CONTINUATION	$31,416
														Subtotal = $502,661

Issue Date FY: 2023 ( Subtotal = $523,605 )
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/3/2023	NON-COMPETING CONTINUATION	$523,605
														Subtotal = $523,605

Issue Date FY: 2022 ( Subtotal = $523,605 )
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/30/2022	NON-COMPETING CONTINUATION	$52,360
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/28/2022	NON-COMPETING CONTINUATION	$471,245
														Subtotal = $523,605

Issue Date FY: 2021 ( Subtotal = $523,605 )
2021	2021	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/29/2021	NEW	$523,605
														Subtotal = $523,605

Grand Total All Awards = $2,073,476

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Characterizing the role of the heme catabolism in tissue damage and inflammation.

Award Number: R01DK125846

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: 03/29/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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