# CELLULAR THERMOSTABILITY AND THERMOTOLERANCE

> **NIH NIH R01** · UNIVERSITY OF WATERLOO · 1990 · $68,672

## Abstract

Hyperthermia has promise as a means of cancer therapy, at least
for tumors refractory to other means of treatment but situated such
that they can be effectively heated to 43-45 degrees.  Most likely
it will be used in combination with radiation or certain chemo-
therapeutic agents.  The molecular effects of hyperthermia are not
well understood, in particular the target (if there is a single
one) of hyperthermia and the molecular basis of thermotolerance are
not known.  These two problems are intimately related since
thermotolerance is probably due to protection or stabilization of
the target.  The specific aims of this proposal are to determine
if the nucleus and subnuclear components (i.e. nuclear matrix and
nucleolus), plasma membrane, and cytoskeleton contain proteins
denaturing at the predicted transition temperature of the critical
target (46.3 degrees), and if the critical target is stabilized in
thermotolerant cells, that is if its denaturation temperature is
shifted to higher values (47.5 to 48.7 degrees depending on the
degree of thermotolerance).  Thermostability will be assayed by
measuring the temperature at which protein denaturation occurs in
these organelles isolated from control and the thermotolerant cells
and in whole CHL V79 cells using high sensitivity differential
scanning calorimetry (DSC) and fluorescence spectroscopy in
selected cases.  These experiments will give information about
which cellular organelles can contain the critical target for
hyperthermia and whether this target, and thus the organelle
containing it, are more thermostable in thermotolerant cells.
Whether or not there is an increase in the level of HSP's in any
organelle demonstrating increased thermostability will be
determined.  Thus, the hypothesis that HSP's are responsible for
thermotolerance by directly stabilizing cellular proteins and
structures will be tested.  In addition, the technique of thermal
gel analysis will be used to determine the molecular weights of all
proteins denaturing during hyperthermia in the isolated organelles.
Thus, it should be possible to identify the critical target and
determine whether or not it is stabilized by HSP's in
thermotolerant cells.

The long term goal is to apply the technique of thermal analysis,
that is the measurement of cellular protein denaturation by DSC and
other physical techniques, to the problem of understanding thermal
damage in mammalian cells and tissue.  Thermal analysis has
potential as a means of analyzing and predicting the
thermostability, hence sensitivity to hyperthermia, of normal and
tumor tissue.

## Key facts

- **NIH application ID:** 3179963
- **Project number:** 5R01CA040251-05
- **Recipient organization:** UNIVERSITY OF WATERLOO
- **SAM.gov UEI:** RHJRA5J1A2B5
- **Principal Investigator:** JAMES R. LEPOCK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1990
- **Award amount:** $68,672
- **Award type:** 5
- **Project period:** 1985-08-01 → 1991-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3179963

## Citation

> US National Institutes of Health, RePORTER application 3179963, CELLULAR THERMOSTABILITY AND THERMOTOLERANCE (5R01CA040251-05). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3179963. Licensed CC0.

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