Perelman School of Medicine at the University of Pennsylvania

Todd Lamitina, Ph.D.
Assistant Professor of Physiology

Department of Physiology
A700 Richards Research Building
3700 Hamilton Walk
University of Pennsylvania
Philadelphia, PA 19104-6085
lamitina@mail.med.upenn.edu

Phone: (215) 898-3223
Fax:  (215) 573-5851

Lab web page:
http://www.med.upenn.edu/lamitinalab/index.shtml


Other Perelman School of Medicine Affiliations
Cell and Molecular Biology Graduate Group
Biochemistry and Molecular Biophysics Graduate Group
Center of Excellence in Environmental Toxicology (CEET)

Degrees
B.S. - Emory University, 1995 Ph.D. - Emory University, 2002

Honors
National Kidney Foundation Fellow, 2003-2006
American Society of Nephrology, Carl W. Gottschalk Award, 2007

Professional Affiliations
Genetics Society of America
American Society of Nephrology

Research Description
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:

1) The 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.

2) Signaling 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.

Publications

Click here for a full list of publications
(searches the National Library of Medicine's PubMed database.)