Dr. Kathleen Kinnally (foreground), Professor of Basic Science and Craniofacial Biology, viewing a cell death
simulation with two research associates, Dr. Sergey Grigoriev and Dr. Ana Paul N. Newton.
Time-lapse view of neural cells disintegrating, showing cells before being injected with cytochrome c (image
with arrows), which sets off cell death, and after. Within 90 minutes (image at bottom right), the cells
shrink, their nuclei condense, and their membranes blister.
Five years after she received a $1.1 million NIH grant, which led
to the discovery of a key early stage of apoptosis (cell death),
Dr. Kathleen Kinnally has received a new four-year, $1.38 million
NIH award to continue her effort to identify proteins that may modulate
the severity of heart attacks, strokes, cancer, and other illnesses
by turning the cell death program on or off.
With the help of the first grant, Dr. Kinnally discovered that
cytochrome c -- a protein that powers cell respiration -- sets off
the cell's destruction when it exits the mitochondrion through a
pore she named the mitochondrial apoptosis-induced channel (MAC).
A protein known as BAX paves the way by punching holes in the membrane.
But another protein, Bcl-2, can block the pore's formation and prolong
cell life beyond its normal span. Mutated cells that don't die contribute
to cancer formation.
These findings were significant because they suggested that treatments
could be developed to alter the course of cell death even before
it begins. Preventing cell death may decrease the severity of heart
attacks and strokes, while initiating cell death can block cancer.
Dr. Kinnally has already identified several medications which appear
to target cell death's earliest stage, such as Dibucaine, a local
anesthetic that rapidly blocks MAC.
But questions remain about how this and other medications interact
with the proteins that spawn cell death from deep inside the thick
mitochondrial membrane. With her new grant, Dr. Kinnally will investigate
whether there may be additional steps involved in opening and closing
the mitochondrial apoptosis-induced channel. She will seek to establish
which other apoptosis proteins may lurk in the mitochondrial membrane,
and how they might be brought under control by medications. To ascertain
how these proteins influence MAC, she will use a technique known
as patch clamping that detects the electrical currents passing through
the channel (high voltage currents signify that the protein is opening
the channel; low voltage currents indicate a closing).
Understanding cell death is particularly relevant to oral health,
since certain conditions, such as gingival enlargement, may result
when cell death and proliferation are out of balance. Oral cancer
is another disease in which cell death plays a key role.