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Poster Full Abstracts - Drosophila Models of Human Diseases
Poster board number is above title. The first author is the presenter
240
to the flies with decreased activity of autophagy, which is a major role in defense against oxidative stress. So more work to explore the association of
frataxin signal pathway and autophagy activity is needed.
399C
A Maternal High Sugar Diet Leads to Metabolic Defects in
Drosophila
Offspring.
Jessica Buescher
1
, Laura Musselman
2
, Riddhi Mitra
1
, Breckyn
Robinson
1
, Thomas Baranski
2
, Jennifer Duncan
1
. 1) Department of Pediatrics, Washington University, St Louis, MO; 2) Department of Medicine,
Washington University, St Louis, MO.
Obesity is a major health concern and leads to chronic health problems. Epidemiological and experimental data indicate the foundation for obesity and
obesity-related diseases may be established early in life as a consequence of a suboptimal maternal-fetal nutritional environment. It is unclear how such a
foundation is established but alterations in epigenetic programming mechanisms may be involved. Our hypothesis is that maternal caloric excess leads to
epigenetic reprogramming in offspring, resulting in alterations in gene expression and increased susceptibility to metabolic disease. To test our hypothesis,
we have established a novel
Drosophila
model in which virgin female
w
1118
Drosophila
are fed a control, low sugar (LS) diet or a high sugar (HS) diet for 7
days before mating with male
Drosophila w
1118
on LS food. Importantly, all progeny develop on the control LS diet. Using established biochemical assays,
we measured body composition of offspring. We observe that wL3 offspring from HS-fed maternal flies exhibit significant increases in glucose, trehalose,
and triacylglycerol (TAG), reductions in cholesterol, hemolymph trehalose and hemolymph TAG, and a delay in pupariation. Interestingly, male offspring
demonstrate more significant alterations in body composition than female offspring. Similar observations were noted in the
Canton S
Drosophila strain.
Microarray analysis on mid-L3 male
Drosophila w
1118
offspring from HS-fed maternal flies and corroboration by tissue-specific qRT-PCR show reduced
expression of midgut-expressed metabolic genes, including genes involved in glucose transport, lipid metabolism and cholesterol homeostasis. Furthermore,
lipid staining of midgut and fat body show alterations in lipid content and lipid particle area, respectively. Taken together, our data indicate that maternal
caloric excess results in metabolic alterations in male offspring exemplified by altered body composition and repression of metabolic regulators.
400A
Using Drosophila to Explore The Architecture of Natural Variations Influencing a Complex Disease Trait.
Bin He
1
, Michael Ludwig
1
, Soo-Young
Park
2
, Pengyao Jiang
1
, Cecelia Miles
1
, Levi Barse
1
, Desiree Dickerson
1
, Sarah Carl
1
, Honggang Ye
2
, Graeme Bell
2
, Martin Kreitman
1
. 1) Department of
Ecology and Evolution, The University of Chicago, Chicago, IL; 2) Department of Medicine, The University of Chicago, Chicago, IL.
Most common human diseases have a multigenic basis with contributions to disease risk and severity by many individual mutations of small effect size.
This makes it difficult to predict the disease risk or to understand the disease mechanism. Here we propose a novel approach to the genetic investigation of a
human complex disease, by combining naturally occurring genetic variations in
Drosophila
and a fly model of human neonatal diabetes. We created a
transgenic line that expresses a mutant (disease-causing) form of human proinsulin in the developing eye imaginal discs, which causes neuro-degeneration in
the adult eyes that mimics the beta cell death in human patients. When we crossed this line to a panel of 180 wild caught inbred lines of
D. melanogaster
(DGRP), a nearly continuous spectrum of disease phenotypes was observed. Applying genome wide association analysis, we identified a 14bp length
polymorphism and a linked SNP in the gene
sfl
to be strongly associated with the eye degeneration phenotype (raw p-value=1.9e-8, Bonferroni corrected
p<0.05). RNAi knock-down of
sfl
confirmed its role of modulating the mutant-proinsulin-dependent eye phenotype. Because the two polymorphisms were
located in the intron, we hypothesize that they exert their effects through changing the expression level of
sfl
. To test this, we are performing pyro-
sequencing to compare the relative expression levels of the two
sfl
alleles in F1 (hybrid) flies. In addition to the major effect gene, a secondary analysis
identified SNPs that interact with the
sfl
locus in the intergenic region between
rpr
and
grim
, two genes that are key regulators of apoptosis in
Drosophila
in
response to cytotoxic stimulus. Our results demonstrated the power of a fly model in studying human complex diseases and provided a potential novel
candidate for diabetes.
401B
Intermittent hypoxia alters the metabolism of Drosophila on a high-fat diet.
Erilynn T. Heinrichsen
1
, Gabriel G. Haddad
1,2
. 1) Pediatrics Dept,
University of California, San Diego, La Jolla, CA; 2) Rady Children’s Hospital, San Diego, CA.
Over 60% of the population in the United States is estimated to be obese or overweight, and with obesity come many disease complications, including
sleep apnea, hypoxia, atherosclerosis, cardiovascular diseases and stroke. Several of these complications also involve hypoxia, yet the fundamental basic
mechanisms underlying the interaction of obesity and hypoxia remain unknown.
Drosophila
, as a model organism, offers tremendous power in uncovering
and studying these mechanisms, given the abundance of molecular tools available to delve into the roles of specific genes and the conservation of
biochemical pathways. We have characterized the phenotype of
Drosophila
on a high saturated fat diet in normoxia and hypoxia using triglyceride levels,
carbohydrate levels, response to stress and lifespan. We have found that, when female flies are put on a high-fat (HF) diet, they have significantly increased
triglyceride and glucose levels and a shortened lifespan. The HF diet allows for increased survival during starvation, but significantly reduces tolerance to
stress conditions such as anoxia and extreme cold. Exposure to intermittent hypoxia (IH), but not constant hypoxia, appears to rescue the response to cold
stress in flies on both diets. This suggests that IH alters the expression of genes involved in cold tolerance in such a way to override the effect of the HF diet.
Microarray studies of these flies have uncovered many candidate genes that may play a role in the phenotype of flies on a HF diet and the underlying
interaction of hypoxia and the HF diet. It appears that immune and metabolic pathways are greatly affected both by a HF diet alone and hypoxia with a HF
diet. We found several genes that were regulated in opposite directions depending on the experimental condition (diet alone or diet with IH), indicating that
while similar pathways may play a role in the phenotype of both conditions, they appear to do so through different mechanisms. These results both confirm
and expand upon our hypothesis that intermittent hypoxia alters the metabolism of
Drosophila
on a high fat diet.
402C
The fat body controls nutrient flux via transcriptional and biochemical mechanisms.
Laura Palanker Musselman, Jill L. Fink, Thomas J. Baranski.
Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO.
Recent epidemiologic studies demonstrate that high glycemic diets increase the risk of developing type 2 diabetes (T2D), but how excess dietary
carbohydrate leads to T2DM remains unclear. Drosophila metabolic pathways are highly conserved with those in vertebrates, but flies offer a simpler, more