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Matthew Rand

TitleAssistant Professor
InstitutionSchool of Medicine and Dentistry
DepartmentEnvironmental Medicine
AddressUniversity of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box EHSC
Rochester NY 14642
 
 Awards And Honors
2011     UVM,"Inventor Hall of Fame"  | For co-invention of a patent with successful commercialization
 
 Overview
Neural developmental toxicity of methylmercury.

Dr. Rand's research focuses on the mechanisms of neural developmental toxicity of the persistent environmental toxin methylmercury (MeHg). Human exposure to MeHg through dietary intake of fish continues to be a major health concern. MeHg preferentially targets the developing nervous system leaving the fetus and young children at greatest risk from exposure.However, considerable uncertainty remains as to the risk of MeHg versus the benefit of essential nutrients in a fish diet. Further uncertainty stems from the wide range of inter-individual variability seen in neurological outcomes, both with MeHg-exposed laboratory animals and in human epidemiological studies of children in fish eating populations.

Our laboratory is engaged in several research projects elucidating molecular, cellular and genetic mechanisms of neural development responsible for variation in tolerance or susceptibility to MeHg toxicity. We are executing transcriptomic and genome wide association methods in the Drosophila model to elucidate fundamental genes that influence tolerance and susceptibility phenotypes in fruit flies developmentally exposed to MeHg. Assays are being conducted at the embryonic and larval/pupal developmental stages using functional assays that target transgenes to neural and non-neural tissues. Candidate genes from Phase I (Cytochrome p450), Phase II (Glutathione S-transferases, GCLm, GCLc) and Phase III (multidrug resistance like protein, MRP1, ABCC1) xenobiotic metabolism pathways have been identified, either through unbiased screens or prospective functional assays, as major effectors of MeHg tolerance and susceptibility. A role for these conventional metabolism genes, specifically in developing neurons, is being characterized. In addition, human homologs of these genes, carrying polymorphic variations known to associate with varied MeHg metabolism in people, are being functionally characterized in this Drosophila system. We are also investigating the role of dietary and nutritional supplements in modifying the MeHg effect in development. With this approach we have identified a protective function for caffeine, and are further investigating the potential protective mechanisms of vitamin E and selenium in MeHg toxicity.

Additional studies are exploiting a novel method developed in the lab to introduce acute doses of small molecules through the eggshell of viable Drosophila embryos. allow us to identify the most MeHg-sensitive window of neural development. These studies, together with studies investigating localization of MeHg in target organs of developing fruit fly larvae with X-Ray fluorescence imaging, are establishing the Drosophila model as a premier platform for basic research in toxicology. In addition, we are initiating studies to develop biomarkers and a protocol to determine MeHg metabolism rates in individual people. These latter studies are aimed at translating our functional studies of Phase I-III metabolism genes in MeHg toxicity to understanding the genetic basis of variation in MeHg susceptibility in populations and in individuals.

 
 Selected Publications
List All   |   Timeline
  1. Rand MD, Montgomery SL, Prince L, Vorojeikina D. Developmental toxicity assays using the Drosophila model. Curr Protoc Toxicol. 2014; 59:1.12.1-1.12.20.
    View in: PubMed
  2. Jebbett NJ, Hamilton JW, Rand MD, Eckenstein F. Low level methylmercury enhances CNTF-evoked STAT3 signaling and glial differentiation in cultured cortical progenitor cells. Neurotoxicology. 2013 Sep; 38:91-100.
    View in: PubMed
  3. Rand MD, Lowe JA, Mahapatra CT. Drosophila CYP6g1 and its human homolog CYP3A4 confer tolerance to methylmercury during development. Toxicology. 2012 Oct 9; 300(1-2):75-82.
    View in: PubMed
  4. Mahapatra CT, Rand MD. Methylmercury tolerance is associated with the humoral stress factor gene Turandot A. Neurotoxicol Teratol. 2012 Jul; 34(4):387-94.
    View in: PubMed
  5. Engel GL, Delwig A, Rand MD. The effects of methylmercury on Notch signaling during embryonic neural development in Drosophila melanogaster. Toxicol In Vitro. 2012 Apr; 26(3):485-92.
    View in: PubMed
  6. Rand MD, Kearney AL, Dao J, Clason T. Permeabilization of Drosophila embryos for introduction of small molecules. Insect Biochem Mol Biol. 2010 Nov; 40(11):792-804.
    View in: PubMed
  7. Mahapatra CT, Bond J, Rand DM, Rand MD. Identification of methylmercury tolerance gene candidates in Drosophila. Toxicol Sci. 2010 Jul; 116(1):225-38.
    View in: PubMed
  8. Rand MD. Drosophotoxicology: the growing potential for Drosophila in neurotoxicology. Neurotoxicol Teratol. 2010 Jan-Feb; 32(1):74-83.
    View in: PubMed
  9. Rand MD, Dao JC, Clason TA. Methylmercury disruption of embryonic neural development in Drosophila. Neurotoxicology. 2009 Sep; 30(5):794-802.
    View in: PubMed
  10. Delwig A, Rand MD. Kuz and TACE can activate Notch independent of ligand. Cell Mol Life Sci. 2008 Jul; 65(14):2232-43.
    View in: PubMed
  11. Rand MD, Bland CE, Bond J. Methylmercury activates enhancer-of-split and bearded complex genes independent of the notch receptor. Toxicol Sci. 2008 Jul; 104(1):163-76.
    View in: PubMed
  12. Cornbrooks C, Bland C, Williams DW, Truman JW, Rand MD. Delta expression in post-mitotic neurons identifies distinct subsets of adult-specific lineages in Drosophila. Dev Neurobiol. 2007 Jan; 67(1):23-38.
    View in: PubMed
  13. Bland C, Rand MD. Methylmercury induces activation of Notch signaling. Neurotoxicology. 2006 Dec; 27(6):982-91.
    View in: PubMed
  14. Delwig A, Bland C, Beem-Miller M, Kimberly P, Rand MD. Endocytosis-independent mechanisms of Delta ligand proteolysis. Exp Cell Res. 2006 May 1; 312(8):1345-60.
    View in: PubMed
  15. Bland CE, Kimberly P, Rand MD. Notch-induced proteolysis and nuclear localization of the Delta ligand. J Biol Chem. 2003 Apr 18; 278(16):13607-10.
    View in: PubMed
  16. Mishra-Gorur K, Rand MD, Perez-Villamil B, Artavanis-Tsakonas S. Down-regulation of Delta by proteolytic processing. J Cell Biol. 2002 Oct 28; 159(2):313-24.
    View in: PubMed
  17. Rand MD, Grimm LM, Artavanis-Tsakonas S, Patriub V, Blacklow SC, Sklar J, Aster JC. Calcium depletion dissociates and activates heterodimeric notch receptors. Mol Cell Biol. 2000 Mar; 20(5):1825-35.
    View in: PubMed
  18. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999 Apr 30; 284(5415):770-6.
    View in: PubMed
  19. Qi H, Rand MD, Wu X, Sestan N, Wang W, Rakic P, Xu T, Artavanis-Tsakonas S. Processing of the notch ligand delta by the metalloprotease Kuzbanian. Science. 1999 Jan 1; 283(5398):91-4.
    View in: PubMed
  20. Rand MD, Lindblom A, Carlson J, Villoutreix BO, Stenflo J. Calcium binding to tandem repeats of EGF-like modules. Expression and characterization of the EGF-like modules of human Notch-1 implicated in receptor-ligand interactions. Protein Sci. 1997 Oct; 6(10):2059-71.
    View in: PubMed
  21. Rand MD, Lock JB, van't Veer C, Gaffney DP, Mann KG. Blood clotting in minimally altered whole blood. Blood. 1996 Nov 1; 88(9):3432-45.
    View in: PubMed
  22. Rand MD, Hanson SR, Mann KG. Factor V turnover in a primate model. Blood. 1995 Oct 1; 86(7):2616-23.
    View in: PubMed
  23. Murray JM, Rand MD, Egan JO, Murphy S, Kim HC, Mann KG. Factor VNew Brunswick: Ala221-to-Val substitution results in reduced cofactor activity. Blood. 1995 Sep 1; 86(5):1820-7.
    View in: PubMed
  24. Kalafatis M, Bertina RM, Rand MD, Mann KG. Characterization of the molecular defect in factor VR506Q. J Biol Chem. 1995 Feb 24; 270(8):4053-7.
    View in: PubMed
  25. Kalafatis M, Rand MD, Mann KG. The mechanism of inactivation of human factor V and human factor Va by activated protein C. J Biol Chem. 1994 Dec 16; 269(50):31869-80.
    View in: PubMed
  26. Kalafatis M, Swords NA, Rand MD, Mann KG. Membrane-dependent reactions in blood coagulation: role of the vitamin K-dependent enzyme complexes. Biochim Biophys Acta. 1994 Nov 29; 1227(3):113-29.
    View in: PubMed
  27. Rand MD, Kalafatis M, Mann KG. Platelet coagulation factor Va: the major secretory platelet phosphoprotein. Blood. 1994 Apr 15; 83(8):2180-90.
    View in: PubMed
  28. Kalafatis M, Rand MD, Mann KG. Factor Va-membrane interaction is mediated by two regions located on the light chain of the cofactor. Biochemistry. 1994 Jan 18; 33(2):486-93.
    View in: PubMed
  29. Kalafatis M, Rand MD, Jenny RJ, Ehrlich YH, Mann KG. Phosphorylation of factor Va and factor VIIIa by activated platelets. Blood. 1993 Feb 1; 81(3):704-19.
    View in: PubMed
  30. Kalafatis M, Krishnaswamy S, Rand MD, Mann KG. Factor V. Methods Enzymol. 1993; 222:224-36.
    View in: PubMed

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