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26 Robert WoodJohnson
Why Sardinia?
ardinians suffer from the world's second-highest rate
of type 1 diabetes--one of the most common chron-
ic childhood diseases, which results from an auto-
immune destruction of insulin-producing beta cells. Since
1990, the Insulin-Dependent Diabetes Mellitus Sardinia
Project has been investigating preclinical phases of type 1
diabetes in a large cohort of people. The goal is to learn
why some people who are genetically at risk for type 1 dia-
betes don't develop the disease.
There's another reason Sardinia is the perfect location for
this research. The island has proved to be a rich source of
data mining for this and other projects because of its isolat-
ed population. It's simpler to investigate the environmental,
immunological, and genetic factors related to the cause and
development of diseases such as type 1 diabetes.
Understanding the Disease
ost autoimmune diseases' genetic susceptibility
is linked to genes in the major histocompatibili-
ty complex (MHC) called human leukocyte anti-
gens (HLA)," says Dr. Denzin. The HLA genes control and
regulate the immune system. "There are HLA class I and
class II genes, and the class II genes have a stronger link to
autoimmunity," she adds. Although 50 percent of genetic
components are linked to HLA molecules, other genes in
the MHC are also involved. "Because HLAs occur in so
many different forms, the diversity makes them difficult to
study in terms of autoimmune disease," says Dr. Denzin.
The Sardinian team was interested in knowing if not only
HLA class II genes but also other genes encoded within the
MHC region were mediating protection from developing
type 1 diabetes.
When the Italian geneticists mapped the genes further,
they discovered that an allele of a gene encoding a protein
that Dr. Denzin's laboratory works on--called DM--is
associated with protection from type 1 diabetes. DM con-
trols the presentation of HLA class II proteins at the cell
surface--known to trigger immunity. Finding a specific
allele of DM that is mediating protection from type 1 dia-
betes suggests that this allele--or version of DM--might in
fact alter this process, thereby leading to protection.
Opening the Door to Collaboration
r. Denzin was approached by Sardinian researchers
Francesco Cucca, MD, professor of medical genet-
ics, University of Sassari, Italy, and director of the
National Research Council of Italy's Institute of Genetic and
Biomedical Research, and Valeria Orrú, PhD, permanent
researcher, University of Cagliari, Italy. "We received an
email from Dr. Orrú expressing an interest in our mouse
model results--where we showed if we altered activity of the
DM protein, we could protect a non-obese diabetic mouse
from diabetes," says Dr. Denzin. "They suggested to us that
modulating DM activity could be the mechanism by which
the people in the Sardinian study are protected from type I
The partnership of the labs was formalized when
Francesca Virdis, PhD, a former Sardinian graduate stu-
dent of Dr. Orrú's, became part of the project, working in
Dr. Denzin's lab as a postdoctoral research fellow. Dr.
Virdis's goal is to use biochemical and cell biological assays
established in Dr. Denzin's lab to answer the question of
altered activity. "If we can show that this DM has altered
function, we could make a significant discovery in type 1
diabetes," says Dr. Denzin.
A Potential Druggable
Target for Type 1 Diabetes
LA class II and DM are needed to fight infec-
tion, so you can't simply get rid of them. What's
important about this idea is that rather than try-
ing to eliminate molecules, we simply change the way they
function," says Dr. Denzin. "DM could be a druggable
target. Potentially changing the way the molecule works
might be enough." A protective genetic variant could lead
to a useful treatment. "Usually people are looking for lots