Friday, April 19, 2024
4/19/2024
Project Summary My lab is interested in the mechanisms that maintain tissue homeostasis, which is critical for proper organ function throughout our lifetimes. Mutations are thought to disrupt cell behaviors and homeostasis, and thus lead to disease. However, recent work demonstrated that aged but phenotypically normal tissues, including skin blood and intestine, are a mosaic of distinct wild-type and mutant clones. Strikingly, 20-30% of cells bear cancer- associated mutations. Intriguingly, we and others have shown that cells containing just one of these cancer- associated mutations outcompete neighboring wild-type cells in the skin. The mechanisms that tolerate but also restrict multiple mutant clones within in aged tissues are not known. We hypothesize that the accumulation of diverse mutant clones promotes healthy aging, as long as their clonal outgrowths are confined, and homeostasis is maintained. Mutations have long been equated with the emergence of pathology and therefore as deleterious alterations that must be eradicated. The high frequency of mutant cells within our normal, aged tissues would imply a continuous and energetically consuming investment to counter their putative negative consequence. Alternatively, mutant cells, particularly those carrying mutations that enhance proliferation/growth, might support or even help tissues maintain homeostasis during aging. Our unconventional hypothesis predicts that tissues benefit from the increased growth introduced by low- level genetic heterogeneity. We propose that a balance is achieved by activation of a mechanism that suppresses aberrant expansion but tolerates and positively utilizes mutant subpopulations. In this scenario, disease arises only after a threshold for tolerance is exceeded, either due to loss of the protective mechanisms or due to an excessive mutational burden. In this Pioneer proposal, we will combine our unique ability to capture behaviors in an intact mammal, to now define the molecular and metabolic consequences of mutations and aging. Understanding how cells evolve their gene expression and metabolic activities in the presence of accumulating mutations and as tissues age will provide fundamental insights into how organs adapt and remain functional throughout our lifetime. Completion of the proposed work will reveal the mechanisms aging skin uses to constrain mutant subpopulations and how acquired mutations in turn impact the aging of skin. These findings could transform our strategies to treat cancer, which are currently aimed at eliminating all mutant cells – which we predict would have unintended, adverse outcomes. The proposed work will shed light not only on tissue homeostasis but also on the problem of aging, which is the major risk factor for nearly every chronic disease.
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