# Project 4: Innate Immunity and Cell Death in ALD

> **NIH NIH P50** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $249,638

## Abstract

ABSTRACT 
Eighteen million Americans abuse alcohol, with alcoholic liver disease (ALD) affecting over 10 million people. 
The development of ALD is a complex process involving both parenchymal and non-parenchymal cells in liver. 
The impact of ethanol on hepatocytes is characterized as a condition of “organelle stress” with multi-factorial 
changes in hepatocellular function accumulating, ultimately leading to hepatocellular death by both apoptosis 
and necrosis/necroptosis. Enhanced inflammation in the liver during ethanol exposure is also an important 
contributor to injury. Accumulating evidence indicates a strong relationship between cell death, inflammation 
and progression of ALD. However, the contribution of specific programmed cell death pathways in 
parenchymal and non-parenchymal cells to ALD is not well understood. Apoptosis is considered to be a less 
inflammatory mode of cell death, while death by necrosis/necroptosis releases multiple pro-inflammatory 
mediators into the local environment. Importantly, programmed cell death has key homeostatic functions; for 
example, activation-induced death of macrophages is a key element in the resolution of inflammation. 
Hepatocyte death via apoptosis is associated with the progression of ALD. Recently, we reported that RIP3- 
mediated necroptotic cell death drives ethanol-induced liver injury in a murine model and that RIP3 expression 
is increased in liver of ALD patients. Taken together, our data indicate that RIP3-dependent necrosome 
formation is critical to the progression of ethanol-induced liver injury. In order to leverage this new mechanistic 
understanding for the development of ALD into therapeutic strategies for treatment or prevention of ALD, here 
we will make use of both in vivo and cell culture models to identify the mechanisms for RIP3-necrosome 
formation during ethanol exposure, as well determine the specific down-stream effector pathways which 
mediate ethanol-induced necroptotic cell death. Our three specific aims are to: 1) Identify the ethanol-induced 
pathways of RIP3/MLKL necrosome formation, 2) Determine the mechanism of necroptotic cell death in 
hepatocytes during chronic ethanol exposure and 3) Understand the differential contribution of RIP3- 
dependent necroptosis in hepatocytes vs myeloid cells in the development ALD. The elucidation of detailed 
mechanisms for ethanol-induced programmed cell death in the liver will provide insight into future 
hepatocellular homeostasis and anti-inflammatory drug design and discovery, particularly related to ALD, as 
well as advance our knowledge of programmed cell death in the liver in general. Importantly, our studies will 
target a neglected therapeutic approach for preventing ethanol-induced inflammation and hepatocellular death.

## Key facts

- **NIH application ID:** 9900711
- **Project number:** 5P50AA024333-05
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** LAURA E. NAGY
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $249,638
- **Award type:** 5
- **Project period:** — → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9900711

## Citation

> US National Institutes of Health, RePORTER application 9900711, Project 4: Innate Immunity and Cell Death in ALD (5P50AA024333-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9900711. Licensed CC0.

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