Project Details
Description
ABSTRACT
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in the United States. NAFLD is a
conglomerate of the relatively nonprogressive non-alcoholic fatty liver (NAFL) and progressive non-alcoholic
steatohepatitis (NASH). While hepatic steatosis is a conserved feature of both NAFL and NASH, the latter is
characterized by liver injury, inflammation, fibrosis, and the risk of liver cancer and cirrhosis. At the present time,
there are no effective noninvasive and scalable screening strategies to distinguish between NAFL and NASH
nor monitor NASH progression. Thus, there is a significant unmet need for biomarkers which are relatively easy
to obtain, can be tested repeatedly over time, can distinguish NAFL from NASH, are pathophysiologically in-
formed, and help risk stratify patients with NASH. Extracellular vesicles (EVs) carry signals from diseased cells
and organs and therefore represent ideal biomarkers for NAFL and NASH. However, the development of EV
based biomarkers has been confounded by several challenges. First challenge relates to the large sample
volume requirements of mass spectrometry approaches traditionally used for EV analysis (e.g. LC-MS/MS). This
limits their utility for the analysis of scarce patient samples. Second challenge lies in the fact that EVs released
from the diseased liver become diluted by circulation and represent only a small subset (~1%) of total EVs
present in peripheral blood. This makes it difficult to identify biomarkers of disease progression or therapy re-
sponse. In this project, we will address the aforementioned challenges by developing novel technologies: 1)
nanoprojectile (NP) secondary ion mass spectrometry (SIMS) that will enable multiplexed analysis of EVs using
microliters of sample and 2) microfluidic organotypic liver cultures that will allow us to harvest undiluted liver EVs
from healthy or diseased tissue.
Upon completion of this project, we will have in hand a powerful mass spectrometry technology for proteomic
and lipidomic analysis of EVs. The identification of EV biomarkers in this project will, in the future, be parlayed
into a blood-based test that will allow to diagnose NAFLD, distinguish NAFL from NASH and help risk stratify
patients. Such a test will replace highly invasive liver biopsy currently used for diagnosis and will revolutionize
the care of patients with NAFLD. It will also allow early diagnosis of NASH in at risk populations.
Status | Active |
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Effective start/end date | 8/1/23 → 5/31/24 |
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases: $706,502.00
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