The metabolic clock as a regulator of cell fate… (R35GM155038) – Project Grant to The Ohio State University

Abstract: Our organs respond dynamically to changes in the body's demands by adapting both their size and activity levels. In these processes, mechanisms governing cell fate decisions, which influence the equilibrium between cell death and cell proliferation, assume crucial roles. Although decades of research have revealed the involvement of cell cycle regulators, epigenetic modulators, metabolic pathways and ionic homeostasis in this complex decision process, we still have major gaps in our understanding of the mechanisms that govern cell fate. These gaps need to be addressed in order to better understand the pathophysiology of many life threatening conditions stemming from the errors of cell fate decision, such as uncontrolled cell death seen in degenerative diseases or uncontrolled cell proliferation in neoplasms and autoimmunity. Our recent work showed that b cell fate is regulated through two spatiotemporally distinct signals, 1- by antigen binding to the b cell receptor (BCR), and 2- via t cell help or pathogen-driven activation of the toll-like receptors (tlrs). While signal-1 primes the cell for activation and proliferation, IT also initiates a short countdown to death that can be halted by a "signal-2". The presence of signal-2 promotes cell survival and proliferation by validating the accuracy of the signal-1, while its absence causes a gradual increase in intracellular calcium leading to mitochondrial dysfunction and cell death. We called this process the 'metabolic clock'. Because mitochondria and calcium homeostasis have been shown to play roles in determining the fate outcomes of many different cell types; our metabolic clock model provides an excellent platform to dissect the mechanisms that govern life and death decisions throughout the body. The overarching goal of our proposal is to unveil the interplay between signals -1 and -2 at the molecular level, with a view towards identifying how metabolic clocks regulate cell fates. Our first project will define how signal-1 induces calcium increase, the main driver of mitochondrial dysfunction, and how this can be prevented by signal- 2 to promote survival and proliferation. Our second project will delineate whether mitochondrial remodeling, under the influence of signals -1 and -2, can modulate the metabolic clock by altering the sensitivity of mitochondria to rising cytoplasmic calcium. Lastly, we will reveal whether the metabolic clock may lead to cell fates other than death or proliferation, such as the induction of an hypofunctional anergic state. We will use transgenic mouse models, novel bone marrow chimeras and human samples to perform integrated sets of biochemical and cellular assays, unraveling how the two signals independently or in combination impact activation of signaling molecules, mitochondrial remodeling, calcium dynamics, and energy production pathways. Altogether, this proposal, bridging basic mechanistic research with in vivo models, will provide a novel perspective of cell fate decision mechanisms, paving the way for new therapeutic approaches to disorders caused by the errors in this process.

Action	Obligated	Date
Amendment	$372,588	Jun 30, 2026
Amendment	$372,588	Jun 17, 2025
Amendment	$372,588	Aug 16, 2024
Original award	$372,588	Aug 16, 2024

The metabolic clock as a regulator of cell fate decision

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