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Principal Investigator: Ali Pirasteh
Organization: UNIVERSITY OF WISCONSIN-MADISON
Fiscal Year: 2024
Award: $683,258
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY/ABSTRACT
The overall goal of this revised proposal is to address the important unmet need for noninvasive detection
and assessment of liver fibrogenesis, the pathologic process resulting in liver scarring and fibrosis. Fibrosis
is the cumulative end-result of all chronic liver diseases (CLD) that affect ~1.5 billion people globally. This study
will be enabled by using positron emission tomography (PET) through specific in-vivo targeting of the activated
(fibrogenic) hepatic stellate cells (HSCs), the cornerstone of liver fibrogenesis and fibrosis.
While non-invasive techniques for assessment of fibrosis have been developed and validated (e.g., magnetic
resonance elastography, MRE), there is lack of a much-needed non-invasive biomarker to measure fibrogenesis,
which is especially significant in the setting of drug-discovery. Development trials and eventual clinical im-
plementation of antifibrotic drugs require non-invasive detection and quantification of active fibrogenesis. As a
current limitation, assessment of treatment response through measuring fibrosis requires several months due to
the time lag between reduction in fibrogenesis and subsequent decrease in fibrosis. Moreover, even if a drug is
effective, MRE may not detect a change in liver stiffness despite improvement in histologic, serologic, and/or
other imaging markers. Hence, non-invasive assessment of liver fibrogenesis is urgently needed.
We have demonstrated successful non-invasive preclinical assessment of liver fibrogenesis through a
fundamentally innovative strategy using PET. Fibroblast activation protein (FAP) is specifically expressed by
activated HSCs. We have demonstrated that in our human-sized model of alcohol-induced liver injury, uptake
of radiolabeled FAP inhibitor (FAPI) on PET directly correlates with fibrogenesis and fibrosis. Moreover, mouse
studies have demonstrated reduced FAP expression with fibrosis reversal. However, there is need for sys-
tematic evaluation of the relationship between FAPI PET and tissue markers of fibrogenesis (1) across all
grades of liver injury, and (2) in both presence and absence of the hepatotoxin. This requires further preclinical
evaluation of FAPI PET in a controlled setting and subsequent translational evaluation in patients. We aim
to (1) Determine the relationship between liver FAPI uptake and tissue markers of fibrogenesis across all stages
of liver injury in our swine model of liver injury; (2) demonstrate that decreasing liver FAPI uptake is a biomarker
for decrease in fibrogenesis and its tissue markers, preceding any reversal in fibrosis; (3) determine the rela-
tionship between liver FAPI uptake and tissue markers of fibrogenesis in a pilot clinical study in CLD patients.
Successful completion of these aims by our unique and highly qualified multidisciplinary team will lay
the foundation for future clinical trials for definitive validation in patients and to fulfill the unmet need of a non-
invasive biomarker for liver fibrogenesis. The development of this biomarker will have a meaningful impact on
the care of ~1.5 billion people with CLD through (1) facilitating the development of antifibrotic pharmacothera-
peutics (2) early detection of fibrogenic liver disease, and (3) monitoring of fibrogenesis in response to treatment.
Terms: <Address><Affect><Alcoholic Liver Diseases><Biological><Biological Markers><Biopsy><Body Tissues><Breathing><Caring><Cell surface><Cessation of life><Cicatrix><Cirrhosis><Clinic><Clinical><Clinical Research><Clinical Study><Clinical Trials><Clinical assessments><Collagen><Death><Deposit><Deposition><Development><Differentation Markers><Differentiation Antigens><Differentiation Markers><Drugs><Early Diagnosis><Evaluation><Family suidae><Fibrosis><Foundations><Future><Goals><Health><Hepatic Cancer><Hepatic Cells><Hepatic Disorder><Hepatic Failure><Hepatic Fibrogenesis><Hepatic Parenchymal Cell><Hepatic Stellate Cell><Hepatocyte><Hepatology><Hepatotoxic effect><Hepatotoxicity><Histologic><Histologically><Histology><Human><Image><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Inflammation><Injury to Liver><Ito Cell><Knowledge><Liver><Liver Cells><Liver Failure><Liver Fibrosis><Liver Toxicity><Liver diseases><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Elastography><Magnetic Resonance Imaging><Malignant neoplasm of liver><Marker Antigens><Measurement><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Methods><Mice><Mice Mammals><Miniature Swine><Minipigs><Modeling><Modern Man><Monitor><Motion><Murine><Mus><NMR Imaging><NMR Tomography><Non-Invasive Detection><Noninvasive Detection><Nuclear Magnetic Resonance Imaging><Outcome><PET><PET Scan><PET imaging><PETSCAN><PETT><Pain><Painful><Pathologic Processes><Pathological Processes><Patients><Persons><Pharmaceutical Preparations><Pigs><Position><Positioning Attribute><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Qualifying><Rad.-PET><Radiolabeled><Research><Research Specimen><Respiratory Aspiration><Respiratory Inspiration><Risk><Sampling><Scars><Serology><Serum Markers><Specimen><Standardization><Suidae><Swine><Techniques><Time><Tissues><Toxic effect on liver cells><Transplantation><Validation><Wisconsin><Zeugmatography><alcohol induced hepatic injury><alcohol induced liver disorder><alcohol induced liver injury><alcohol related liver disease><alcohol-associated liver disease><alcohol-induced hepatic dysfunction><alcohol-induced liver disease><alcohol-induced liver dysfunction><alcohol-mediated liver dysfunction><alcohol-mediated liver injury><alcohol-related liver disease><alcoholic liver injury><bio-markers><biologic><biologic marker><biomarker><biomarker development><chronic hepatic disease><chronic hepatic disorder><chronic liver disease><chronic liver disorder><cirrhotic><clinical implementation><developmental><drug development><drug discovery><drug/agent><early detection><effective therapy><effective treatment><elastic imaging><elasticity imaging><elastography><ethanol induced hepatic injury><ethanol induced liver disorder><ethanol induced liver injury><ethanol liver disease><ethanol-induced hepatic dysfunction><ethanol-induced liver disease><ethanol-induced liver dysfunction><ethanol-mediated liver dysfunction><ethanol-mediated liver injury><fibroblast activating factor><fibroblast activation protein><fibroblast proliferation factor><fibroblast-activating factor><fibrogenesis><fibrotic liver><hepatic body system><hepatic damage><hepatic disease><hepatic fibrosis><hepatic inflammation><hepatic injury><hepatic organ system><hepatic stiffness><hepatic toxicity><hepatocellular injury><hepatopathy><hepatotoxicant><hepatotoxin><hepatoxicity><imaging><imaging biomarker><imaging marker><imaging-based biological marker><imaging-based biomarker><imaging-based marker><improved><in vivo><inflamed liver><inhibitor><innovate><innovation><innovative><inspiration><liver cancer><liver damage><liver disorder><liver fibrogenesis><liver imaging><liver inflammation><liver injury><liver malignancy><liver scanning><liver stiffness><malignant liver tumor><mini pig><mini-swine><miniswine><multidisciplinary><new approaches><novel approaches><novel strategies><novel strategy><pig model><piglet model><porcine><porcine model><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><pre-clinical><pre-clinical assessment><pre-clinical evaluation><preclinical><preclinical assessment><preclinical evaluation><prevent><preventing><prognostic><protein expression><public health relevance><radiolabel><radiolabeling><radiolabels><radiologically labeled><radiotracer><response to therapy><response to treatment><specific biomarkers><suid><swine model><therapeutic response><therapy response><transplant><treatment response><treatment responsiveness><uptake><validations>