Research
Evolution of Alpha Crystallin Structure and Function
My lab is currently
studying the evolution and function of the vertebrate small heat shock protein
alpha crystallin. This protein has long been known to play an important
structural role in the ocular lens, but in the 1980's the gene was sequenced
and found to be a small heat shock protein. These proteins protect cells
when they are experiencing stressfull conditions, such as changes in
temperature. But why is this stress protein made by the lens?
Human lens
The human lens is one of the
few structures in your body that continues to grow throughout your life.
Additional layers of cells are added to the lens like the layers of an
onion. Unfortunately, these cells lose their nuclei and therefore are
unable to make proteins. This means that the oldest parts of your lens
contain proteins as old as you are. Typically, the body replaces proteins
as they age because they accumulate damage that makes them unfold, or
denature. Denatured proteins tend to stick together, or aggregate, which
in the lens can lead to cataracts, one of the leading causes of blindness.
Normal lens
Cataractous lens
Experiments in the 1980's
showed that alpha crystallin has the ability to prevent this aggregation of
denatured proteins. It does this by acting as a molecular chaperone,
binding to denatured proteins before they can aggregate. This
ability has only been demonstrated in vitro, but it is also thought to occur
within the lens. If this is so, alpha crystallin may play an important
role in preventing cataracts. Recently it was shown that a natural human
mutation in the gene that codes for one of the two versions of alpha crystallin
leads to cataracts. It is now thought that alpha crystallin may play a
protective role in other parts of the body as well. Increased levels of
this protein are found in the nervous system in conjunction with Mad Cow's
disease, Alzheimer's disease and Multiple Sclerosis. Heart muscle cells
also increases production of alpha crystallin in some diseases.
Essentially all alpha
crystallin research is performed on mammals. However, my lab is
investigating the structure and function of this protein from different
vertebrate groups. More can be learned about alpha crystallin's role in
animal physiology by comparing the different versions of this protein found in
different types of animals. We are currently extending the knowledge of
alpha crystallin function by examining the version of this protein found in
fishes. Fishes are significantly different from mammals in several
ways. But most importantly for our research, most fishes are ectothermic,
which means they do not maintain a constantly high body temperature like
endothermic mammals. Variation in their body temperature allows us to
examine how alpha crystallin structure and function adapts to a changing
thermal environment.
By investigating alpha
crystallin in fishes we hope to:
1. Gain a better
understanding of the changing physiological function of alpha crystallin in
vertebrate evolution.
2. Determine the
functionally important regions of the protein.
3. Understand how alpha
crystallin structure and function adapts to different environmental demands.
We previously cloned and
sequenced the two alpha crystallin genes from the zebrafish. Both
sequences have been deposited in a database called Genbank. Click here
to see the sequence for zebrafish alpha A-crystallin, and click here
to see the sequence for zebrafish alpha B-crystallin. To read our
publication of the zebrafish alpha A-crystallin gene click here.
the zebrafish, Danio rerio
We recently finished a
comparative study of how well the zebrafish alpha crystallins protect against
protein aggregation compared to the same proteins from the human lens. Click here
to see our latest paper describing some of these data. Most recently we have extended our
study of fish alpha crystallins to two new species. The Antarctic toothfish, which lives in waters as cold as -2
degrees Celsius, is allowing us to examine how alpha A-crystallin has adapted
to function in very cold temperatures.
This research is being done in collaboration with researchers at the
University of Illinois at Urbana-Champaign. We are also studying a local Ohio fish, the blunt-nose
minnow, to see how alpha A-crystallin adapts to the temperate conditions found
here in North America. The goal of
these studies is to identify slight structural changes in alpha A-crystallin that
modify its ability to prevent protein aggregation. While this work is being done in fishes, it has a direct
impact on the study of human cataracts.
Check back to this page to see updates on
this research.
Student
Researchers: Where are they now?
Undergraduates at Ashland University play
a large role in this research effort. Past and current undergraduate
research assistants are listed below, along with the location of graduates. 
Current
Students:
Molly Hawke, Stephanie Morgan, Jenny Vacha
Former
Students:
Rebecca
Richards (2003-2004)
National Institutes of Health, Research Fellowship
Mike
Danko (2003-2004)
The Ohio State
University, School of Medicine
Amber
Smith (2003-2004
Ashland University, Masters program in Education
Jason
Dahlman (2001-2003)
The Ohio State
University, PhD program in Integrated Bioscience
Kelly
Margot (2002)
Medical
University of South Carolina, PhD program in Marine Biotechnology
Mindy
Stechschulte (2000-2001)
Ohio University,
Physical Therapy Program
Sara
Low (2000-2001)
Johns Hopkins University, Nursing Program
Stephanie
Runkle (1999-2000)
University of Michigan, Ann Arbor, PhD program in
Toxicology
Julie
Hill (1999-2000)
The Ohio State University, Optometry School