Kevin Strange, Ph.D.

Kevin Strange, Ph.D.President and ProfessorMDI Biological Laboratory

Research Areas

Regenerative Biology and Medicine

Education

Ph.D., University of British Columbia, Zoology/Physiology, 1983 B.S., University of California at Davis, Zoology/Physiology, 1977

Contact

gro.lbidm@egnartsk

207 -288-9880 ext 136

159 Old Bar Harbor RD
PO Box 35
Salisbury Cove, ME 04672

Program in Environmental Stress Biology

Research in my laboratory focuses on defining the molecular mechanisms and genetic pathways by which animal cells sense and maintain salt and water balance. Our studies employ the roundworm C. elegans, a non-mammalian model organism that provides powerful experimental advantages for defining the genetic bases of fundamental physiological processes. These advantages include a fully sequenced genome, genetic tractability, and ease and economy of manipulating gene function. Our studies employ multiple methodological approaches including quantitative light and electron microscopy, molecular biology, functional genomics analyses, forward genetic screening, and genome-wide RNA interference screening.

Recent work in my laboratory has shown that cell dehydration causes rapid damage to cytoplasmic proteins. Ongoing studies focus on defining the mechanisms utilized by cells to detect, degrade, and repair proteins damaged by acute dehydration. We are also defining the mechanisms utilized by cells to protect proteins from damage during prolonged exposure to dehydrating conditions and the sensing and signaling pathways that activate genes required for cellular salt and water balance.

Program in Membrane Biology

ClC genes encode ubiquitous proteins and that move Cl- ions and protons across cell and organelle membranes. Mutations in several human ClC genes cause kidney, bone, and muscle disorders. My laboratory utilizes the genetically-tractable model organism C. elegans to define the physiological consequences of ClC activity. Our studies employ a variety of methodological approaches including patch clamp electrophysiology, protein structure modeling, quantitative light microscopy, molecular biology, protein chemistry, functional genomics analyses, forward genetic screening and genome-wide RNA interference screening. Ongoing studies focus on defining the signaling pathways and phosphorylation dependent structural mechanisms that regulate a cell cycle and cell volume sensitive C. elegans ClC Cl- channel.

Mechanisms of Cellular Osmosensing and Osmotic Stress Induced Damage Repair

Cellular osmotic homeostasis is a fundamental requirement for life. All cells are exposed to osmotic challenges brought about by changes in intracellular solute flux and/or perturbations in extracellular osmolality. Most mammalian cells are protected from extracellular osmotic challenges by the kidney, which tightly regulates blood ionic and osmotic concentrations. Renal medullary cells are an important exception to this generalization and are subjected normally to extreme osmotic stress by the renal concentrating mechanism.

Cells maintain osmotic homeostasis by the tightly regulated gain and loss of salt and organic solutes termed organic osmolytes and by detecting and repairing osmotic stress-induced damage. The transport and metabolic pathways that mediate animal cell osmoregulatory solute fluxes are well described. However, little is known about the signaling mechanisms by which animal cells detect osmotic perturbations, about the types of cellular and molecular damage induced by osmotic stress, and about how this damage is detected, repaired, and prevented.

The nematode C. elegans lives in an osmotically unstable environment and is well adapted to cope with continuous and extreme osmotic stress. We have developed C. elegans as a novel genetically and molecularly tractable model system in which to define fundamental mechanisms of animal cell osmosensing and osmotic homeostasis. Our recent studies have demonstrated for the first time that hypertonic stress and associated water loss causes rapid and extensive protein damage in vivo and that genes encoding the ubiquitin-proteasome and lysosome protein degradation machinery are essential for survival under hypertonic conditions. We have also made the novel and intriguing observation that disruption of protein synthesis serves as a signal that activates osmosensitive gene expression. Our current work builds on these new findings and addresses three questions that have broad biological and pathophysiological significance. How does disruption of protein synthesis activate transcription of genes required for organic osmolyte accumulation? What are the quality control mechanisms utilized by cells to detect, degrade, and repair proteins damaged by hypertonic stress? What are the mechanisms by which acclimation to hypertonic stress suppresses hypertonicity-induced protein damage? Students working in the laboratory will use a wide variety of cell biological, molecular, and genetic approaches to address these questions. Approaches utilized include transgenesis, genome-wide RNA interference screening, quantitative fluorescence microscopy analysis of living C. elegans, and protein chemistry.

Rhythmic Ca²⁺ signaling: keeping time with microRNAs. Strange K, Yin VP. Curr Biol. 2012 Dec 4;22(23):R1000-1. doi: 10.1016/j.cub.2012.10.024. PMID: 23218004 [PubMed - in process]

CLC anion channel regulatory phosphorylation and conserved signal transduction domains. Miyazaki H, Yamada T, Parton A, Morrison R, Kim S, Beth AH, Strange K. Biophys J. 2012 Oct 17;103(8):1706-18. doi: 10.1016/j.bpj.2012.09.001. Epub 2012 Oct 16.PMID:23083714 [PubMed - in process]

GCN-2 dependent inhibition of protein synthesis activates osmosensitive gene transcription via WNK and Ste20 kinase signaling. Lee EC, Strange K. Am J Physiol Cell Physiol. 2012 Dec 15;303(12):C1269-77. doi: 10.1152/ajpcell.00294.2012. Epub 2012 Oct 17. PMID:23076791 [PubMed - indexed for MEDLINE]

Characterization of the proteostasis roles of glycerol accumulation, protein degradation and protein synthesis during osmotic stress in C. elegans. Burkewitz K, Choe KP, Lee EC, Deonarine A, Strange K. PLoS One. 2012;7(3):e34153. doi: 10.1371/journal.pone.0034153. Epub 2012 Mar 28.PMID:22470531[PubMed - indexed for MEDLINE]

Differential regulation of a CLC anion channel by SPAK kinase ortholog-mediated multisite phosphorylation. Miyazaki H, Strange K. Am J Physiol Cell Physiol. 2012 Jun 15;302(12):C1702-12. doi: 10.1152/ajpcell.00419.2011. Epub 2012 Feb 22.PMID:22357738[PubMed - indexed for MEDLINE]

High-throughput screening and biosensing with fluorescent C. elegans strains. Leung CK, Deonarine A, Strange K, Choe KP. J Vis Exp. 2011 May 19;(51). doi:pii: 2745. 10.3791/2745.PMID:21633332 [PubMed - indexed for MEDLINE]

Hypertonic stress induces rapid and widespread protein damage in C. elegans. Burkewitz K, Choe K, Strange K. Am J Physiol Cell Physiol. 2011 Sep;301(3):C566-76. doi: 10.1152/ajpcell.00030.2011. Epub 2011 May 25.PMID:21613604 [PubMed - indexed for MEDLINE]

Putting the pieces together: a crystal clear window into CLC anion channel regulation. Strange K. Channels (Austin). 2011 Mar-Apr;5(2):101-5. Epub 2011 Mar 1.PMID: 21317557 [PubMed - indexed for MEDLINE]

C. elegans STK39/SPAK ortholog-mediated inhibition of ClC anion channel activity is regulated by WNK-independent ERK kinase signaling. Falin RA, Miyazaki H, Strange K. Am J Physiol Cell Physiol. 2011 Mar;300(3):C624-35. doi: 10.1152/ajpcell.00343.2010. Epub 2010 Dec 15.PMID:21160027[PubMed - indexed for MEDLINE].

Cell physiology at the Mount Desert Island Biological Laboratory: a brief look back and forward. Strange K. Am J Physiol Cell Physiol. 2011 Jan;300(1):C1-5. doi: 10.1152/ajpcell.00448.2010. Epub 2010 Nov 10. PMID: 21068363 [PubMed - indexed for MEDLINE]

View All Publications
  • Heejung Kim, Ph.D., Postdoctoral Fellow
  • Rebecca Morrison, Lab Manager
  • Angela Parton, Senior Technician
  • Toshiki Yamada, Ph.D., Postdoctoral Fellow