# Autophagy regulation of apoptosis and necroptosis within cell populations

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2023 · $350,977

## Abstract

An important unsolved question in cell death is to understand why different cells within a population vary in
their responses. Which cells will live or die and what determines exactly how they die after exposure to a
death stimulus? These questions underlie fundamental cell fate decisions and also have important practical
ramifications, for example, during cancer therapy when non-heritable, heterogeneous responses to anti-cancer
drugs underlie the eventual acquisition of resistance to therapy. Heterogeneity in cell responses can be driven
by stable genetic differences between cells, which are easy to understand. However, such differences also
occur even in genetically homogeneous cell populations. What underlies these differences? More important,
can we manipulate these effects? Previous work supported by this grant discovered that even in a
homogeneous population of cells under unstressed conditions, there is extensive variation in the amount of
autophagic flux, which in turn predicts the outcome to future treatment with a death stimulus. And, in the last
funding period, we discovered a specific mechanism by which autophagy controls the apoptosis threshold and
a quite different mechanism by which the autophagy machinery can control necroptosis. Building on these
previous studies, we hypothesize: autophagy controls apoptotic and necroptotic thresholds by regulating
Mitochondrial Outer Membrane Permeabilization (MOMP). And, this explains cell death variation between cells
in a population. We will test this hypothesis by completing the following aims using a variety of new
approaches including the first method that allows optogenetic regulation of autophagy. Specific Aim 1. Test if
autophagy variation before and after a death stimulus controls heterogeneity in apoptosis responses in a cell
population. Specific Aim 2. Determine how autophagy regulates necroptosis. By completing these aims, we
will gain new insights into the interplay between two major forms of programmed cell death (apoptosis and
necroptosis) and uncover how autophagy regulates these processes.

## Key facts

- **NIH application ID:** 10604388
- **Project number:** 5R01CA150925-14
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** James V Degregori
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $350,977
- **Award type:** 5
- **Project period:** 2010-04-19 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10604388

## Citation

> US National Institutes of Health, RePORTER application 10604388, Autophagy regulation of apoptosis and necroptosis within cell populations (5R01CA150925-14). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10604388. Licensed CC0.

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