Perelman School of Medicine Affiliations
Cell and Molecular Biology Graduate Group
Biochemistry and Molecular Biophysics Graduate Group
Center of Excellence in Environmental Toxicology (CEET)
- Emory University, 1995 Ph.D. - Emory University, 2002
National Kidney Foundation Fellow, 2003-2006
American Society of Nephrology, Carl W. Gottschalk Award,
Genetics Society of America
American Society of Nephrology
I am interested in the molecular mechanisms by which
animal cells sense and respond to environmental stressors.
My lab approaches these questions using genetic, genomic,
and biochemical approaches in the nematode C. elegans.
Currently, the lab is focused on defining the molecular
mechanisms underlying the osmotic stress response.
The cellular osmotic stress response is essential for
all forms of cellular life, but the molecular events
that underlie this process have never been genetically
dissected in animals. The soil dwelling nematode C.
elegans offers numerous experimental advantages for
these studies, such as forward and reverse genetic
tractability, transparent body architecture, simple
transgenic methods, and a highly annotated complete
genome sequence. The lab is currently addressing two
important problems using this system:
role of protein damage in activation of osmosensitive signaling
pathways. To chronically adapt to hypertonic stress, all
organisms accumulate organic osmolytes, which are non-ionic,
osmotically active solutes that balance osmotic gradients
and stabilize protein structure. Worms accumulate the organic
solute glycerol to adapt to hypertonicity. The C. elegans
genome encodes two glycerol-3-phosphate dehydrogenase (gpdh)
genes, which catalyze the rate limiting step in glycerol
biosynthesis. Worms expressing a gpdh-1:GFP transgene exhibit
no GFP expression under standard lab culture condition.
However, rapid GFP expression is induced following
exposure to hypertonic stress. Since other stressors
do not affect the expression of gpdh-1:GFP, this reporter
function as a specific in vivo monitor for the activation
state of signaling pathways controlling osmosensitive
gene expression. Using genome-wide RNAi screening approaches,
we have identified at least 122 gene knockdowns that
result in the constitutive activation of gpdh-1:GFP
expression. The majority of these genes normally function
to regulate protein folding, protein synthesis, and
protein degradation. These data have suggested the
unique hypothesis that the accumulation of specific
types of misfolded proteins, which is a major consequence
of hypertonic stress, functions as a signal to activate
osmosensitive signaling pathways in animals. Currently,
we are testing if hypertonicity disrupts protein stability
and if accumulation of destabilized and aggregating
proteins can directly activate osmosensitive gene expression.
pathways that regulate osmosensitive gene expression. The
signaling events that regulate osmotic stress responses
have been extensively explored using genetic and genomic
approaches in bacteria, yeast, and plants. Using osmosensitive
gpdh-1:GFP expression as a phenotypic readout, we have
begun to apply these approaches to molecularly dissect
the osmotic stress response in C. elegans. Forward genetic
screening has identified numerous loss-of-function and
gain-of-function mutants that regulate gpdh-1 expression.
Using a quantitative large object flow cytometer (the “Worm Sorter”),
we are performing both RNAi and forward genetic screens
to identify kinases, transcription factors, and other
novel signaling molecules that transduce osmotic stress
signals. Using genetic approaches such as epistasis
and suppression, we will assemble this pathway to understand
how, when, and where these genes act relative to one
another. In the future, the application of these approaches
to other stress response pathways, such as heat and
oxidative stress, will allow us to build an integrative
picture of environmental stress signaling.
T. Functional Genomic Approaches in C. elegans. Methods
Mol Biol 351: 127-138, 2006.
T, Huang CG and Strange K. Genome-wide RNAi screening
identifies protein damage as a regulator of osmoprotective
gene expression. Proc Natl Acad Sci U S A 103: 12173-12178,
X, Xing J, Lorin-Nebel C, Estevez AY, Nehrke K, Lamitina
T and Strange K. Function of a STIM1 Homologue in C. elegans:
Evidence that Store-operated Ca2+ Entry Is Not Essential
for Oscillatory Ca2+ Signaling and ER Ca2+ Homeostasis.
J Gen Physiol 2006.
CG, Agre P, Strange K and Lamitina T. Isolation of C.
elegans Deletion Mutants Following ENU Mutagenesis and
Thermostable Restriction Enzyme PCR Screening. Mol Biotechnol
32: 83-86, 2006.
ST and Strange K. Transcriptional targets of the DAF-16
insulin signaling pathwayprotect C. elegans from extreme
hypertonic stress. Am J Physiol Cell Physiol 2004.
ST, Morrison R, Moeckel GW and Strange K. Adaptation
of the nematode Caenorhabditis elegans to extreme osmotic
stress. Am J Physiol Cell Physiol 286: C785-C791, 2004.
Click here for
a full list of publications
(searches the National Library of Medicine's PubMed database.)