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Laurie                         Read

Laurie K. Read PhD

Department of Microbiology and Immunology

Professor

Specialty/Research Focus

Gene Expression; Microbial Pathogenesis; Molecular and Cellular Biology; Molecular genetics

 
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Professional Summary:

Trypanosomes are members of the kinetoplastid protozoa, which cause enormous medical and economic distress in Third World countries. They are eukaryotic parasites which are the causative agents for diseases such as Sleeping Sickness, Leishmaniasis, and Chagas disease. In our laboratory, we study the parasitic trypanosome, Trypanosoma brucei. In addition to being of great medical and economic importance, T. brucei is an excellent model system for the study of posttranscriptional gene regulation, because regulation at the level of transcription is essentially absent in this organism. Our primary focus is on two RNA processing events in T. brucei: RNA editing and RNA turnover. A third related area of research is the mechanism by which posttranslational modification of RNA binding proteins by arginine methylation regulates RNA editing, trafficking, turnover, and trans-splicing.

RNA editing is a novel mechanism for regulating gene expression in which sequence information is added to mRNAs after transcription by specific uridine addition and deletion. The editing of mRNAs in T. brucei is so extensive that uridine insertions can double the size of the transcript. Editing generates translatable messages by creating the open reading frames as well as proper initiation and termination signals. The phenomenon is of fundamental importance in understanding how genetic information can be stored and processed. We are studying the mechanisms used by T. brucei to regulate editing of specific RNAs, particularly as they are differentially edited between life cycle stages. We identified the first RNA editing regulatory factor, a mitochondrial RNA binding protein termed RBP16. Genetic disruption of RBP16 in insect stage trypanosomes causes massive down-regulation of a specific subset of editing events. Currently, we are using a combination of biochemical and genetic approaches to elucidate the mechanisms by which RBP16 regulates editing of specific RNAs and to determine its regulatory scope throughout the trypanosome life cycle. Our approaches include gene knock-down of RBP16 and RBP16-associated proteins in both insect and mammalian life cycle stages, analysis of the biochemical effects of RBP16 on RNA editing in vitro, and yeast-two hybrid and TAP affinity chromatography approaches to identification of RBP16 binding partners. Future directions will involve the identification and characterization of additional RNA editing regulatory proteins.

The levels of translatable mRNAs are dictated by the balance between transcription rates and mRNA turnover rates. Because transcription is largely unregulated in T. brucei, the mechanisms by which mRNA turnover is controlled take on enhanced importance. We have identified two pathways for mRNA turnover in T. brucei mitochondria. One pathway is specific for polyadenylated RNAs and depends on the UTP concentration, while the second pathway is independent of the polyadenylation state of the RNA and nucleotide concentrations. We developed an in vitro RNA turnover system that allows us to directly examine the effects of specific 3? sequences on RNA degradation. We are also using this system as a starting point for biochemical purification of the proteins that catalyze and regulate RNA turnover pathways. In addition, we used a bioinformatics approach to identify trypanosome homologs of the yeast mitochondrial degradosome proteins DSS1 (an exoribonuclease) and SUV3 (and RNA helicase). Biochemical and genetic studies are underway to determine the roles of these proteins in turnover of the various classes of mitochondrial RNAs.

Methylation of arginine residues in proteins is a posttranscriptional modification whose important in areas such as signal transduction, RNA trafficking, mRNA splicing, and transcription is just recently becoming apparent. Interestingly, a very large percentage of proteins that undergo arginine methylation are RNA binding proteins. Given that gene regulation in trypanosomes relies so heavily on RNA processing, our hypothesis is that arginine methylation is especially important in these organisms. We showed that multiple proteins in T. brucei are subject to arginine methylation (including the mitochondrial RNA binding protein, RBP16). In addition, we identified two genes encoding the protein arginine methyltransferases (PRMTs) that catalyze this modification. Studies are currently underway to determine the effect of PRMT down-regulation in trypanosomes on growth rate as well as on specific RNA processing events. We are identifying novel PRMT substrates in T. brucei using both yeast two-hybrid and affinity chromatography methods. Finally, mutation of the methylated arginine residues in RBP16 will allow us to determine how this modification modulates the function and macromolecular interactions of this protein.

Education and Training:
  • PhD, Cellular and Molecular Physiology, Tufts University School of Medicine (1990)
  • MA, Cell Biology and Physiology, University of California at Santa Barbara (1985)
  • BA, Biology, Boston University (1982)
Employment:
  • Professor, University at Buffalo (2006-present)
  • Associate Professor, University at Buffalo (2000–2006)
  • Assistant Professor, University at Buffalo (1994–2000)
  • Postdoctoral Fellow, Seattle Biomedical Research Institute, University of Washington (1990–1994)
Awards and Honors:
  • New Investigator in Molecular Parasitology Award, Burroughs Wellcome Fund (1996)
  • National Research Service Award (1991)
  • Predoctoral Fellowship, Berlex Laboratories (1990)
  • Travel Award, American Society for Cell Biology (1989)
  • National Research Service Award, Public Health Service, National Institutes (1988)
  • Edwin W. Pauley Foundation Grant-in-Aid (1983)

Research Expertise:
  • post-transcriptional gene regulation: In our laboratory we study the eukaryotic parasite Trypanosoma brucei, which is the causative agent of human African trypanosomiasis, also known as African sleeping sickness. This disease is invariably fatal if not treated, and current drugs are toxic and difficult to administer, and resistance is developing. Essential and novel processes in this parasite may serve as starting platforms for new drug therapies. In addition to being of great medical and economic importance, T. brucei is also an excellent model system for the study of posttranscriptional gene regulation, because regulation at the level of transcription is essentially absent in this organism. The primary focus of our laboratory is on the mechanisms and regulation of two RNA processing events in T. brucei: RNA editing and RNA turnover. A third related area of research is the mechanism by which posttranslational modification of RNA binding proteins by arginine methylation modulates RNA processing, stability, and translation. RNA editing RNA editing is a novel mechanism for regulating gene expression in which sequence information is added to mRNAs after transcription by specific insertion and deletion of uridine residues. Editing generates translatable messages by creating the open reading frames as well as proper initiation and termination signals. The phenomenon is of fundamental importance in understanding how genetic information can be stored and processed, and it is an essential process in trypanosomes. We identified several RNA binding proteins and ribonucleoprotein complexes that act as RNA editing accessory factors, and which are essential for the editing of specific RNAs or classes of RNAs. We are currently using biochemical, genetic, and genomic approaches to determine the molecular mechanisms by which these factors modulate RNA-RNA, RNA-protein, and protein-protein interactions. RNA turnover The levels of translatable mRNAs are dictated by the balance between transcription rates and mRNA decay rates. The decay rates of specific RNAs are determined by both cis-acting sequences within the mRNA itself as well as trans-acting proteins that interact with those RNA sequences. We have developed an in vitro RNA turnover system for identification of cis- and trans-acting factors that modulate mitochondrial RNA decay rates. We identified small edited RNA sequences that dramatically affect the rate of RNA decay, and showed that 3’ poly(A) tails differentially affect the decay rate of an RNA depending on its editing status. We are using biochemical and bioinformatic approaches to identify 1) exoribonucleases that catalyze decay of different RNA classes and 2) RNA binding proteins that recognize cis-acting elements and regulate RNA turnover pathways. We are also performing genetic studies in trypanosomes to define the roles of these trans-acting factors in mitochondrial gene regulation. Protein arginine methylation Methylation of arginine residues in proteins is a posttranslational modification whose importance in areas such as signal transduction, RNA trafficking, RNA processing, and transcription has recently become apparent. Interestingly, a very large percentage of proteins that undergo arginine methylation are RNA binding proteins. We have identified and characterized five protein arginine methyltransferases that catalyze this process in T. brucei. We have also identified numerous RNA binding proteins that undergo arginine methylation. Studies are currently underway to determine how methylation of RNA binding proteins affects their functions in posttranscriptional gene regulatory processes.
Grants and Sponsored Research:
  • September 2011–August 2016
    Training in microbial pathogenesis
    NIH NIAID
    Role: Principal Investigator
    $141,112
  • August 2012–July 2016
    Regulation of RNA editing in Trypanosoma brucei(RO1AI061580)
    NIH NIAID
    Role: Principal Investigator
    $250,000
  • May 2010–April 2015
    Protein arginine methylation in trypanosomes
    NIH NIAID
    Role: Principal Investigator
    $250,000
  • May 2008–April 2013
    Cis- and trans-acting factors in mitochondrial RNA decay
    NIH NIAID
    Role: Principal Investigator
    $250,000

Evaluative Studies and Case Reports:
Journal Articles:
See All (59 Total) >
Books and Book Chapters:
  • Stuart, K., Corell, R.A., Goringer, H.U., Koslowsky, D.J., Myler, P.J., Laurie Read, Riley, G.R., Shu, H.-H., Souza, A.E.. RNA editing in Trypanosoma brucei: gRNA diversity and redundancy. Plant Mitochondria. 1993.

Professional Memberships:
  • American Society for Microbiology (2000)
  • American Society for Microbiology; Western NY Branch (1998)
  • RNA Society (1995)
  • AAAS (1992)
Presentations:
  • "RNA editing and stability in Trypanosoma brucei" Department of Oral Biology, SUNYAB (2002)
  • "Disruption of RBP16 gene expression differentially affects editing of multiple RNAs in Trypanosoma brucei" Molecular Parasitology Meeting XII (2001)
  • "Molecular interactions involving the guide RNA binding protein, RBP16" Gordon Conference on RNA Editing (2001)
  • "Molecular interactions involving the guide RNA binding protein, RBP16" Second International Conference on Proteins that Bind RNA (2001)
  • "Molecular interactions involving the mitochondrial Y-box protein, RBP16" Second International Conference on Proteins that Bind RNA (2001)
  • "Polyadenylation and UTP regulate Trypanosoma brucei mitochondrial mRNA turnover in vitro" Molecular Parasitology Meeting XII (2001)
  • "The trypanosome homolog of human p32 interacts with RBP16 and stimulates its gRNA binding activity" Molecular Parasitology Meeting XII (2001)
  • "Characterization ofmitochondrial ribonuclease activities from Trypanosoma brucei" Molecular Parasitology Meeting XI (2000)
  • "Gene expression in trypanosome mitochondria: unique aspects of RNA processing" Dept. of Cellular and Molecular Physiology, Tufts University School of Medicine (2000)
  • "Mitochondrial ribonuclease activities from Trypanosoma brucei" Fifth Annual Meeting of the RNA Society (2000)
  • "Structure-function analysis of the mitochondrial Y-box protein RBP16" Fifth Annual Meeting of the RNA Society (2000)
  • "Structure-function analysis of the mitochondrial Y-box protein RBP16" Molecular Parasitology Meeting XI (2000)
  • "UTP-dependent and -independent pathways of mRNA turnover in Trypanosoma brucei mitochondria" Fifth Annual Meeting of the RNA Society (2000)
  • "UTP-dependent and -independent pathways of mRNA turnover in trypanosome mitochondria" Gordon Conference on Mitochondria and Chloroplasts (2000)
  • "UTP-dependent and -independent pathways of mRNA turnover in trypanosome mitochondria" Gordon Conference on Mitochondria and Chloroplasts (2000)
  • "Binding properties of the Trypanosoma brucei gRNA-binding protein RBP16" Molecular Parasitology Meeting X (1999)
  • "RNA editing in African trypanosomes" Roswell Park Cancer Research Institute (1999)
  • "Trypanosoma brucei RBP16 associates with gRNA and rRNA and is present in multicomponent complexes" Fourth Annual Meeting of the RNA Society (1999)
  • "UTP stimulates degradation of polyadenylated RNA in Trypanosoma brucei mitochondria" Fourth Annual Meeting of the RNA Society (1999)
  • "UTP stimulates degradation of polyadenylated RNA in Trypanosoma brucei mitochondria" Molecular Parasitology Meeting (1999)
  • "UTP stimulates degradation of polyadenylated RNAs in Trypanosoma brucei mitochondria" Molecular Parasitology Meeting X (1999)
  • "A eukaryotic Y-box protein from Trypanosoma brucei with gRNA binding activity" Molecular Parasitology Meeting IX (1998)
  • "Mitochondrial gene expression in Trypanosoma brucei" CAMBI Research Exchange Series, SUNYAB (1998)
  • "Mitochondrial RNA processing in Trypanosoma brucei" Burroughs Wellcome Fund New Investigators Meeting (1998)
  • "The role of polyadenylation in the mitochondria of Trypanosoma brucei" Molecular Parasitology Meeting (1998)
  • "The role of polyadenylation in Trypanosoma brucei mitochondria" Third Annual Meeting of the RNA Society (1998)
  • "Trypanosoma brucei RBP16: A Y-box family member that binds guide RNA and acts as an RNA chaperone" Third Annual Meeting of the RNA Society (1998)
  • "RNA editing in African trypanosomes" microbial Pathogenesis Graduate Group Fall Research Forum, SUNYAB (1997)
  • "Purification and characterization of a mitochondrial RNA binding protein from Trypanosoma brucei" Molecular Parasitology Meeting (1997)
  • "Kinetoplastid RNA editing" SUNYAB Department of Biochemistry (1995)
  • "RNA editing complexes in Trypanosoma brucei" SUNYAB Department of Biological Sciences (1995)
  • "Potential RNA editing complexes in Trypanosoma brucei" Molecular Parasitology Meeting (1994)
  • "RNA editing in African trypanosomes" West Virginia University Medical School (1994)
  • "RNA editing in African trypanosomes" SUNYAB School of Medicine (1994)
  • "RNA editing in African trypanosomes" Medical College of Virginia (1994)
  • "RNA editing in African trypanosomes" University of Montana (1994)
  • "RNA editing in African trypanosomes" South Carolina Medical University (1994)
  • "RNA editing in African trypanosomes" Arizona State University (1994)
  • "RNA editing in African trypanosomes" University of Vermont School of Medicine (1994)
  • "In vitro formation of gRNA-and mRNA-containing ribonucleoprotein complexes in Trypanosoma brucei" Cold Spring Harbor RNA Processing Meeting (1993)
  • "In vitro formation of mitochondrial ribonucleoprotein particles containing gRNA, mRNA, and specific gRNA binding proteins" West Coast Kinetoplastid Conference (1993)
  • "Analysis of RNA editing in Trypanosoma brucei" Molecular Parasitology Meeting (1992)
  • "New insights into RNA editing in trypanosomes" Seattle Protozoology Conference (1992)
  • "RNA editing in Trypanosoma congolense" American Society of Tropical Medicine and Hygiene Meeting (1992)
  • "RNA editing in Trypanosoma congolense: Developmental regulation and conservation of edited RNA, but not DNA, sequence between T. congolense and T. brucei" Molecular Parasitology Meeting (1992)
See All (45 Total) >
Service Activities:
  • Preliminary (Qualifying) Examination Committee; Committee Member (2001)
  • Committee on Promotions to Unqualified (tenured) Ranks; Committee Member (2001)
  • First Annual Western New York RNA Graduate Group Spring Forum; Co-Chair (2001)
  • Search Committee, Molecular Biology Faculty, Dept. of Biological Sciences; Committee Member (2001)
  • Immunology Faculty Search Committee; Committee Member (2000)
  • Graduate Group on RNA; Organizing Committee Member (2000)
  • School of Medicine and Biomedical Sciences Buswell Fellowship Committee; Committee Member (2000)
  • Preliminary (Qualifying) Examination Committee; Committee Member (1999)
  • Microbial Pathogenesis Training Grant Implementatiion Committee; Committee Member (1999)
  • Microbial Pathogenesis Graduate Group Fall Forum Organizing Committee; Chairman (1998–1999)
  • Microbial Pathogenesis Graduate Group Fall Forum Organizing Committee; Co-Chair (1997–1998)
  • Preliminary (Qualifying) Examination Committee; Committee Member (1997)
  • Founding Member and Organizer, Buffalo Area RNA Club; meets monthly with members from UB North and South Campuses, Roswell Park Cancer Research Institute, and VA Hospital; Co-Chair (1997)
  • Income Fund Reimbursable Committee; Committee Member (1997)
  • Seminar Committee; Committee Member (1997)
  • Center for Advanced Molecular Biology and Immunology Steering Committee; Member (1996–2000)
  • Immunology/Bacteriology Faculty Search Committee; Committee Member (1996)
  • Preliminary (Qualifying) Examination Committee; Committee Member (1996)
  • Cirriculum/Graduate Affairs Committee; Committee Member (1996)
  • Howard Hughes Undergraduate Biological Sciences Program; Student Mentor (1995–2000)

Clinical Specialties:
Clinical Offices:
Insurance Accepted:

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Contact Information

249 Biomedical Research Building
Buffalo, NY 14214
Phone: (716) 829-3307
Email: lread@buffalo.edu


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