MECHANISMS OF REDUCED PROTEIN DEGRADATION WITH AGE

Project: Research project

Project Details

Description

The candidate is a junior researcher with considerable experience in
intracellular protein degradation and some training in aging research.
In order to become a fully independent researcher studying changes in
protein metabolism with age, an additional supervised training period
will be very important. Dr. J. Fred Dice, due to his extensive research
experience in protein degradation in aging, would be the ideal mentor
for this training. The research project will be carried out at Tufts
University which offers a stimulating scientific environment and a well-
established research program in cellular metabolism and physiology. The
proposed four year career development plan is oriented to: i) confer the
candidate strong background in aging, ii)improve her research
experience, including learning new experimental approaches,
iii)facilitate productive collaborations with well established
researchers and iv)develop her teaching, training and group leader
skills.

The main goal of the research project is to identify the cause(s) of the
decrease in the specific degradation of cytosolic proteins in lysosmers
with age. The reduction of this degradative system may contribute to
the cytosolic accumulation of abnormal proteins in senescent cells and
the subsequent generalized failure of many cellular functions. The
selective lysosomal pathway is induced in response to nutrient
deprivation, and it is mediated by a cytosolic heat shock protein of
73KDa (hsc73), that stimulates binding of substrates to the lysosomal
membrane, and by a lysosomal hsc73, essential for the import of
substrate proteins. The characterization of the different components
involved in this lysosomal uptake, and the further comparison of their
levels in young and old rats, will be decisive in identifying the origin
of the lysosomal failure with age. The steps followed by the substrates
of this pathway will be analyzed in an in vitro system with isolated rat
liver lysosomes. Immunological procedures and protein interaction
assays will be use to determine changes in levels or activity of the
components of the system with age. Overexpression of some of those
components in cultured cells will be used to determine their
participation in the selective degradation of proteins in lysosomes and
to analyze the contribution of their age-dependent changes to some of
the characteristics of senescent cells. These studies will also
evaluate the possible reversibility of the lysosomal defect with age.
StatusFinished
Effective start/end date5/1/984/30/99

Funding

  • National Institute on Aging

ASJC

  • Geriatrics and Gerontology
  • Molecular Medicine
  • Molecular Biology
  • Biochemistry
  • Cell Biology

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