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Molecular Magnetic Resonance of Hepatic Fibrogenesis

Award Number: R01DK121789
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: 07/03/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Molecular Magnetic Resonance of Hepatic Fibrogenesis - A. Specific Aims Identification of high-risk populations suitable for screening and chemoprevention of hepatocellular carcinoma (HCC) has been proposed as an effective and efficient strategy to impact HCC-related mortality. Screening and earlier detection of HCC has had some impact on HCC mortality. However, the absence of tools to accurately predict which patients will progress to HCC remains a significant barrier to development of effective chemoprevention agents. Progress in prediction of who will progress to HCC and whether chemoprevention is likely to be effective would have a major clinical impact. Liver fibrosis is a common pathway shared by all progressive chronic liver diseases that raise risk for HCC, regardless of the underlying etiologies. Many lines of evidence suggest that increased fibrosis and fibrogenesis are independent predictors of HCC transformation, and that reducing liver fibrosis reduces HCC risk. Our lab has developed molecular probes for noninvasive, quantitative imaging of liver fibrosis and fibrogenesis throughout the entire liver. With a type I collagen targeted peptide-based MR probe we showed that we could accurately stage liver fibrosis in 6 different rodent models. We developed a second type of probe in prior work funded by this grant: molecular MR probes that target the aldehyde-containing allysine residue on oxidized collagen and showed that we could specifically quantify fibrogenesis (fibrotic disease activity). In this Renewal, we propose to expand this toolbox further and develop a third novel probe that targets inflammation associated with fibrogenesis (IAF). This probe is based on the low relaxivity Fe2+-PyC3A chelate which is activated by rapid oxidation to high relaxivity Fe3+-PyC3A in the presence of peroxidases released during inflammation and which then binds to allysine residues that are present during fibrogenesis, retaining the probe and its high relaxivity signal at the site of IAF. We will deploy these three probes (fibrosis, fibrogenesis, IAF) to characterize the combinations of these biochemical features that best predict transformation to HCC in rat and mouse models. Next, we will use molecular MR for real-time monitoring of response to chemoprevention agents that have been proven effective in preclinical models, and to guide effective dosing. The overarching goal of this project is to leverage molecular imaging of fibrosis to accurately predict risk of progression to HCC, and real-time monitoring of efficacy of interventions that reduce the risk. Aim 1. Develop a turn-on molecular probe to detect fibrogenesis when it is associated with inflammation. 1.1. Synthesize a small focused library of allysine-targeted, Fe2+-PyC3A probes 1.2. Screen the probes for relaxivity in the presence/absence of peroxidase, target affinity, non-specific binding, and allysine binding kinetics to a model proteiny 1.3. Confirm the ability of the IAF probe to detect inflammation associated fibrogenesis in a mouse model of NASH/fibrosis/HCC (choline-deficient, l-amino acid-defined, high-fat diet and a single dose diethylnitrosamine (DEN) injection; DEN-CDAHFD) 1.4. Demonstrate the specificity of the IAF probe for inflammation with fibrogenesis compared to fibrosis with minimal inflammation in rat diethylnitrosamine (DEN) models of acute inflammation. Aim 2. Define which combination of total liver collagen, liver fibrogenesis, and IAF assessed early in the course of disease by molecular MRI is predictive of worse disease progression 2.1. Image DEN-CDAHFD mice with moderate or severe liver fibrosis using CM-101 (collagen targeted probe), Gd-1,4 (fibrogenesis probe), and the AIF probe from Aim 1 and then follow these animals and determine which animals develop HCC. Compare the accuracy of the three molecular MR methods performed early in the course of disease to predict worse disease progression and to predict HCC transformation. Aim 3. Demonstrate that molecular MR can provide an accurate as


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: 2026 ( Subtotal = $706,400 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	3/10/2026	NON-COMPETING CONTINUATION	$706,400
														Subtotal = $706,400

Issue Date FY: 2025 ( Subtotal = $706,400 )
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	4/17/2025	NON-COMPETING CONTINUATION	$706,400
2025	2022	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $706,400

Issue Date FY: 2024 ( Subtotal = $717,569 )
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	2/19/2024	COMPETING CONTINUATION	$717,569
2024	2022	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/9/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $717,569

Issue Date FY: 2022 ( Subtotal = $792,133 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/17/2022	NON-COMPETING CONTINUATION	$661,029
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/23/2022	SUPPLEMENT FOR EXPANSION	$131,104
														Subtotal = $792,133

Issue Date FY: 2021 ( Subtotal = $758,502 )
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/21/2021	SUPPLEMENT FOR EXPANSION	$131,104
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/20/2021	NON-COMPETING CONTINUATION	$627,398
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	5/24/2021	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $758,502

Issue Date FY: 2020 ( Subtotal = $651,816 )
2020	2020	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/19/2020	NON-COMPETING CONTINUATION	$651,816
														Subtotal = $651,816

Issue Date FY: 2019 ( Subtotal = $651,816 )
2019	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/3/2019	NEW	$651,816
														Subtotal = $651,816

Grand Total All Awards = $4,984,636

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Molecular Magnetic Resonance of Hepatic Fibrogenesis

Award Number: R01DK121789

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: 07/03/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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