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J. Eric Russell, M.D. Medline
search Abramson Research Center, Room 316F
Scientific Focus: Regulation and function of human globins Program Summary: Hemoglobin is a heterotetrameric metaloprotein comprising two a-like and two b-like globin subunits. The expression of specific globin subunits during human development follows an established pattern: z and e globins in embryos, a and g globins in fetuses, and a and b globins in adults. A major research effort in the Russell laboratory is directed towards defining the properties of hemoglobins that incorporate embryonic globin subunits, including Hbs z2e2, z2b2, and a2e2. The impetus for this activity is the possibility that these hemoglobins might subserve therapeutically valuable roles in adults with disorders of globin gene expression, such as thalassemias or sickle cell anemia. Using complex transgenic/knockout mice as bioreactors we have generated and purified each of these unusual human hemoglobins and established many of their basic properties. Ongoing experiments are designed to evaluate the anti-sickling properties of these hemoglobins, their important biochemical characteristics, and their physiological role in human development. A second major research effort is directed towards understanding the molecular mechanisms that contribute to the developmental silencing of embryonic globin genes. We have found that full silencing of the z-globin gene in adults requires post-transcriptional events that regulate z-globin mRNA stability. In more recent work we have established important structural and functional links between the mechanisms that stabilize the a- and b-globin mRNAs. Our current investigations focus on the mechanisms through which the e-, g-, and b-like globin mRNAs are stabilized, as well as the possibility that these properties are actively regulated to optimize function of the mature erythrocyte. A thorough understanding of these mechanisms would permit the design of therapies intended to dysregulate globin gene expression through manipulation of mRNA stability. In addition to studies relating to globin gene expression and function, we have initiated a series of pilot experiments focused on establishing the mechanism through which the prothrombin 3'UTR G20210A mutation effects hyperprothrombinemia. New investigators would be encouraged to participate in ongoing research, or to design new projects relating to our interests in the post-transcriptional control of globin gene expression or the function of embryonic globins. If you want to learn more: Morales, J., Russell, J.E., and Liebhaber, S.A. (1997) Destabilization of human a- globin mRNA by translation anti-termination is controlled during erythroid differentiation and is paralleled by phased shortening of the poly(A) tail. J. Biol. Chem. 272:6607-13. Russell, J.E., Morales, J., Makeyev, A., and Liebhaber, S.A. (1998) Sequence divergence in the 3' untranslated regions of human z- and a-globin mRNAs mediates a difference in their stabilities and contributes to efficient a-to-z gene developmental switching. Mol. Cell. Biol. 18:2173-83. Russell, J.E., and Liebhaber, S.A. (1998) Reversal of lethal a and b thalassemias in mice by expression of human embryonic globins. Blood 92:3057-3063. He, Z., Lian, L., Asakura, T., and Russell, J.E. (2000) Functional effects of replacing human a and b globins with their embryonic globin homologues in defined hemoglobin heterotetramers. Br. J. Heme. 109:882-890. He, Z., and Russell, J.E. (2001) Expression, purification, and characterization of human hemoglobins Gower-1 (z2e2), Gower-2 (a2e2), and Portland-2 (z2b2) assembled in complex transgenic/knockout mice. Blood 97:1099-1105. Yu, J, and Russell, J.E. (2001) Structural and functional analysis of an mRNP complex that mediates the high stability of human b-globin mRNA. Mol. Cell. Biol. 21:5879-5888. |
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