Why This
Project?
In the
past, the effects of ionizing radiation on humans has been attributed
in great part to its ability to damage DNA, which transmits
information from cell to cell, and generation to generation.
Damaged DNA can lead to cell death or perpetuate the damage
to daughter cells and to future generations. In addition to
the information contained with the genome (i.e. DNA sequence),
information directing cell behavior and tissue function is also
stored outside the DNA. The success in cloning sheep from the
DNA contained in the nucleus of an adult cell shows how important
signals from the outside are in defining how the genome is expressed.
This so-called epigenetic regulation is evident in that the
same human genome gives rise to over 30 organs and 300 distinct
cell types. These patterns of gene expression are called phenotype.
Phenotype is as much a function of cell environment as an expression
of genotype. The basic decision of a cell to either proliferate,
differentiate or die is an integrated response to its genome,
its history and its local environment.
Project
Goals:
- Better
understand how ionizing radiation alters tissue function by
studying how radiation affects extracellular sources of information
and multicellular interactions.
- Understand
how TGF-ß contributes to the radiation effects and how
radiation effects on the tissue contributes to the development
of breast cancer.
- Determine
whether TGF- ß can eliminate abnormal cells in irradiated
tissue, that in turn suppresses neoplastic behavior.
- Evaluate
the effect of radiation dose and fractionation on the phenotype
of non-malignant human mammary epithelial cells and preneoplastic
mammary epithelial cells.
- Determine
whether epigenetic mechanisms perpetuate an irradiated phenotype
from generation to generation of human mammary epithelial
cells.
- Test
the alternative hypothesis that irradiated cells communicate
phenotype via extracellular signaling.
Research
Approach:
We will
use digital microscopy to study cell culture models and mouse
models. We will continue to develop a bioinformatics framework
called BioSig to integrate the acquisition, analysis and annotation
of the digital images.
Expected
Outcomes:
Understanding
radiation effects in terms of coordinated multicellular responses
that affect cellular fate decisions may require reevaluation
of radiation dose and risk concepts but may also provide avenues
for intervention.
Our broad
hypothesis is that radiation-induced bystander effects and genomic
instability are manifestations of this homeostatic process.
Bystander effects, exhibited predominantly following low dose
or non-homogenous radiation exposures, are evidence of indirect
and direct cell-cell communication that modulate cellular repair
pathways and death programs. Genomic instability, evidenced
generally after relatively high doses of ionizing radiation,
results from persistent disruption of cell communication and/or
the microenvironment, leading to the accumulation of aberrant
cells.
Additional
Information:
We have
shown that irradiated tissues promote tumor formation independent
of the past history of the cells in the culture. Our studies
have focused on a protein called transforming growth factor-
ß (TGF- ß) as a key player in tissue radiation response.
We have demonstrated that TGF- ß is an extracellular sensor
of damage that orchestrates the damage responses of many cell
types. Our recent data indicate that one important consequence
of TGF- ß signaling is elimination of abnormal cells via
a process of cell death called apoptosis, but that it can also
promote abnormal behavior in irradiated cells insensitive to
its apoptotic signal.
|
