[R35] Cellular and molecular mechanisms governing stem cell resilience
Ente: National Institute of General Medical Sciences
Scadenza: 2031-04-30
Importo max: 415.686 EUR
Paese: US
Descrizione
Biological resilience is the ability of organisms to rebound from various stresses including tissue injury and
exposure to toxins that cause DNA damage. Stem cells offer a potentially powerful line of defense against
these insults through their ability to restore tissues, yet stem cells themselves are susceptible to deterioration
from overuse or age, as a result of recurring cell divisions. To understand how stem cells can resist these types
of insults, my lab studies one of the most resilient animals known, freshwater planarians. Planarians are
famous for their ability to regenerate entire animals from tiny tissue fragments, due to an abundant population
of stem cells. These stem cells appear to be inexhaustible: not only can they differentiate into any cell type, but
they also maintain animal integrity throughout thousands of generations of asexual reproduction. Here, we will
leverage the unique biology of planarian stem cells to identify conserved mechanisms responsible for their
ability to regenerate repeatedly and to overcome significant genotoxic stress. The proposed experiments
integrate prior findings with innovative tool development to advance our understanding of stem cell biology in
this ideal invertebrate animal model. In the next five years, our work will occur in three primary research
directions: (1) To regenerate entire animals, stem cell differentiation must be precisely coordinated. We
recently identified a new signaling pathway involving the Roundabout receptor and Anosmin-1 that instructs
stem cell differentiation to a specific body region. We will characterize the biochemistry and cell biology of this
pathway to determine how stem cell activity is sculpted during regeneration. (2) Ionizing radiation causes DNA
damage that is lethal to stem cells. We discovered two strategies that enable stem cells to overcome what was
previously thought to be certain death. In the process, we uncovered key molecular differences in DNA
damage response pathways in planarians that may reveal new strategies for DNA repair in less resilient
animals. We will use molecular tools combined with genetic manipulations to mark sites of DNA damage and
elucidate fundamental aspects of DNA repair, cell cycle progression, and apoptosis that enable planarians to
withstand and recover from high doses of ionizing radiation. (3) To fully understand molecular and cellular
aspects of regeneration, we need the ability to modify the genome modification, a technique that has not yet
been developed in planarians. Building on preliminary findings, we will advance this technology using a
stepwise approach, enabling the development of tools that can be applied across many studies. Together,
these three lines of investigation will illuminate mechanisms that equip planarian stem cells with extreme
plasticity and persistence throughout many thousands of divisions. Our work will inform strategies to mitigate
stem cell exhaustion or enhance regeneration in other animals.
Istituzione: CORNELL UNIVERSITY
PI: Carolyn Elizabeth Adler
Progetto: 1R35GM163946-01
Settori: National Institute of General Medical Sciences
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