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Principal Investigator: Lin, Kyle Matthew
Institute Receiving Award University Of Chicago
Location Chicago, IL
Grant Number F30ES035279
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Jul 2023 to 30 Jun 2027
DESCRIPTION (provided by applicant): Project Summary Environmental temperature dictates biology. Animals use their thermal environments to guide their migration, circadian rhythms, growth, feeding, and sex determination: essential behaviors now threatened by changing climates. Warming temperatures likewise challenge human health. About 1 in 100 deaths globally stem from heat-related causes, and such mortality is rising. Beyond lethal heatstroke, more mild heat affects human health in far more common and pervasive ways. Heat <40°C alters and dysregulates human physiology down to the cellular level, particularly in immune cells. Such sublethal heat shocks occur in hyperthermia and heat illness, as well as frequently in fever: a systemic heat shock which regulates the immune system during infection. Yet even in the well-known context of fever, we lack understanding of how human cells sense sublethal heat shock. The cell biology of extreme heat shock >40°C is well-characterized, but far less is understood about sublethal, fever-range temperatures <40°C. However, we do know that certain immune cells upregulate heat shock protein expression in response to fever. The induction of heat shock proteins, or the heat shock response, occurs in eukaryotes when heat activates transcription factor Hsf1, via titration of its repressor (heat shock protein Hsp70) away from Hsf1. This titration is caused by the generation of new, heat shock-induced substrates for Hsp70 to bind. These substrates, i.e. the upstream sensors of heat, are unidentified in sublethal heat shock. We hypothesize biomolecular condensates are these substrates which help cells sense sublethal heat shock. Condensation, or reorganization of proteins and RNA into larger foci, occurs in response to environmental stimuli across species from yeast to humans. Our group showed recently that heat-induced condensates are Hsp70 substrates in yeast. We hypothesize that sublethal heat shock-induced condensates are Hsp70 substrates in humans, enabling cells to sense and respond to such fever-range temperatures. It is not known what proteins condense in human cells at these temperatures, nor if such condensates might be Hsp70 substrates. Moreover, in any species, we lack molecular-scale understanding of how condensates and Hsp70 interact. We are poised to unlock exactly this knowledge using a complement of biochemical, microscopic, and molecular-level approaches. First, we will uncover protein condensation in human cell lines at fever-range temperature, using the established sedimentation-mass spectrometry method of our group. Second, we will observe directly how condensates and Hsp70 interact at the molecular scale, using single-molecule microscopy. Together, these aims will help us elucidate fundamentally how cells sense and respond to sublethal heat shock.
Science Code(s)/Area of Science(s) Primary: 01 - Basic Cellular or Molecular processes
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications No publications associated with this grant
Program Officer Daniel Shaughnessy