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UW School of Dentistry

Department: Oral Health Sciences

Peter Byers

Interests

We are pursuing several lines of research: the characterization of mutations in type I collagen genes (COL1A1 and COL1A2) that give rise to forms of osteogenesis imperfecta and other disorders, the identification and characterization of mutations in the type III collagen gene (COL3A1) which give rise to Ehlers-Danlos syndrome type IV, characterization of mutations in other genes (e.g., COL5A1, COL5A2, PLOD1 and the N-terminal procollagen protease) that result in other forms of connective tissue disorder, identification of proteins in the intracellular and extracellular processing pathways that identify abnormal collagen proteins, and the mechanisms of mRNA processing in collagen genes to predict the outcome of splice site mutations. In addition, we are searching for other genes that may give rise to phenotypes of osteogenesis imperfecta, and determining the rate and genetic basis of parental mosaicism for mutations in these genes.

The majority of mutations in the COL1Al and COLlA2 genes that cause OI result in substitution for glycines within the triple helix. Most of the remainder alter splice sites. Our studies of the mutations suggest that in some instances the order of exon splicing may determine the effects of splice mutations; as a consequence we are studying the order of intron removal in such cell strains. One of the most puzzling aspects of OI has been the failure to identify mutations in all affected individuals. Using long amplification regions, we have noted low level splice defects in some such patients that result in the production of only a small amount of abnormal molecules due to the presence of 5-10% abnormal mRNA species as a consequence of mutations outside the canonical splice site sequences. However, it is clear that some mutations reside outside these two gene.

We have now characterized almost 400 mutations in our families with EDS type IV. These are more heavily weighted to point mutations that result in substitutions for glycine residues within the triple helix of the molecule than mutations that alter splice site integrity. Some mutations prohibit mRNA transport from the nucleus when introns that contain termination codons are included. These findings suggest that there is a link between splicing and nuclear recognition of premature termination codons that may be different from the recognition process that leads to cytoplasmic nonsense-codon mediated mRNA decay. The mechanisms of recognition of these structures is being pursued.

Similar approaches are being taken to disorders which result from several other genes involved in connective tissue biogenesis.

Publications

  1. Persikov AV, Pillitteri RJ, Amin P, Schwarze U, Byers PH, Brodsky B (Oct 2004) Stability related bias in residues replacing glycines within the collagen triple helix (Gly-Xaa-Yaa) in inherited connective tissue disorders., Human Mutation, 24(4)330-7
  2. Byers PH (Jul 2004) Determination of the molecular basis of Marfan syndrome: a growth industry., The Journal of Clinical Investigation, 114(2)161-3
  3. Schwarze U, Hata R, McKusick VA, Shinkai H, Hoyme HE, Pyeritz RE, Byers PH (May 2004) Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway., American Journal of Human Genetics, 74(5)917-30
  4. Kaiser FJ, Brega P, Raff ML, Byers PH, Gallati S, Kay TT, de Almeida S, Horsthemke B, Ludecke HJ (Feb 2004) Novel missense mutations in the TRPS1 transcription factor define the nuclear localization signal., European Journal of Human Genetics : Ejhg, 12(2)121-6
  5. Chamberlain JR, Schwarze U, Wang PR, Hirata RK, Hankenson KD, Pace JM, Underwood RA, Song KM, Sussman M, Byers PH, Russell DW (Feb 2004) Gene targeting in stem cells from individuals with osteogenesis imperfecta., Science, 303(5661)1198-201
  6. Palmeri S, Mari F, Meloni I, Malandrini A, Ariani F, Villanova M, Pompilio A, Schwarze U, Byers PH, Renieri A (Jun 2003) Neurological presentation of Ehlers-Danlos syndrome type IV in a family with parental mosaicism., Clinical Genetics, 63(6)510-5
  7. Pace JM, Corrado M, Missero C, Byers PH (Mar 2003) Identification, characterization and expression analysis of a new fibrillar collagen gene, COL27A1., Matrix Biology : Journal of the International Society for Matrix Biology, 22(1)3-14
  8. Takahara K, Schwarze U, Imamura Y, Hoffman GG, Toriello H, Smith LT, Byers PH, Greenspan DS (Sep 2002) Order of intron removal influences multiple splice outcomes, including a two-exon skip, in a COL5A1 acceptor-site mutation that results in abnormal pro-alpha1(V) N-propeptides and Ehlers-Danlos syndrome type I., American Journal of Human Genetics, 71(3)451-65
  9. Marlowe A, Pepin MG, Byers PH (Jun 2002) Testing for osteogenesis imperfecta in cases of suspected non-accidental injury., Journal of Medical Genetics, 39(6)382-6
  10. Chuman H, Trobe JD, Petty EM, Schwarze U, Pepin M, Byers PH, Deveikis JP (Jun 2002) Spontaneous direct carotid-cavernous fistula in Ehlers-Danlos syndrome type IV: two case reports and a review of the literature., Journal of Neuro-ophthalmology : the Official Journal of the North American Neuro-ophthalmology Society., 22(2)75-81

Frank Roberts

Interests

Regulation of inflammation in human adult periodontitis and other chronic inflammatory diseases, effects of chronic neutropenia on oral health, and biology and imaging of the dental implant.

Publications

  1. Schuler RF, Janakievski J, Hacker BM, O’Neal RB, Roberts FA.*  Effect of implant surface and grafting on implants placed into simulated extraction sockets: a histologic study in dogs.  Int J Oral Maxillofac Implants. 2010 Sep-Oct;25(5):893-900.
  2. Roberts FA, Hacker BM, Oswald TK, Mourad PD, McInnes C.  Evaluation of the use of ultrasound within a power toothbrush to dislodge oral bacteria using an in vitro Streptococcus mutans biofilm model.  Am J Dent. 2010 Apr;23(2):65-9.
  3. Mourad PD, Roberts FA, McInnes C.  Synergistic use of ultrasound and sonic motion for removal of dental plaque bacteria.  Compend Contin Educ Dent. 2007 Jul;28(7):354-8.
  4. Smith, J., Wong, C.S., Salamonik, E.B., Hacker, B.M., McDonald, R.A., Mancl, L.A., Williams, B.J., Ibrahim, A., and Roberts, F.A.* 2006  Sonic Tooth Brushing Reduces Gingival Overgrowth in Renal Transplant Recipients.  Pediatr. Nephr. Nov;21(11):1753-9.
  5. Cai, S., Fatherazi, S., Presland, R., Belton, C., Roberts, F.A., Goodwin, P., Schubert, M., and Izutsu, K. 2006. Evidence that TRPC1 Contributes to Calcium-Induced Differentiation of Human Keratinocytes. Pflugers Arch. Apr;452(1):43-52.
  6. Wang IC, Roberts FA.* 2005  Adjunctive Periodontal Therapies.  Pract. Proced. Aesthet. Dent. May;17(4):245-6.
  7. Hacker, B.M. and Roberts, F.A.* 2005.  Genetics of Periodontal Disease Pathogenesis.  Pract. Proced. Aesthet. Dent. 17(2):97-102 (cover article).

Douglas Ramsay

Ramsay

Doug was born and raised in Pennsylvania where he received a B.A. in psychology from Franklin & Marshall College in 1979 and a D.M.D. from the University of Pennsylvania in 1983.  He came to the UW in 1983 as a senior fellow and in 1985 entered the UW’s NIH-funded Dentist-Scientist Training Program, which supported his doctoral studies in psychology (PhD, 1988) and specialty training in orthodontics (MSD, 1990).  He joined the UW faculty in 1990 and is currently Chair of the Department of Oral Health Sciences and the Associate Dean for Research and Faculty in the School of Dentistry.  

Doug is a professor of Orthodontics, Oral Health Sciences and Pediatric Dentistry.  In addition to receiving numerous NIH research grants, he was also the recipient of a Research Career Development Award from the National Institute of Dental and Craniofacial Research (NIDCR).  Doug is a Diplomate of the American Board of Orthodontics and a member of the Edward H. Angle Society of Orthodontists.  Doug is the Director of the UW’s Regional Clinical Dental Research Center and is currently the Director of the T90/R90 NIDCR-supported institutional training grant at the UW School of Dentistry.  Doug has directed courses in the predoctoral dental and graduate dental specialty programs, supervised patient care in the graduate orthodontics clinic, and been Chair of numerous thesis committees.

Dr. Ramsay teaches and supervises students at the undergraduate, graduate, and post-doctoral levels. Each year he directs a didactic seminar for the graduate students in Pediatric Dentistry and Orthodontics and provides guest lectures in other courses. As a board-certified orthodontist, he teaches and supervises patient care in the graduate orthodontics clinic throughout the year.

Dr. Ramsay’s research interests are broad and he has a record of conducting both basic and clinical research. A primary research interest of his is in the area of behavioral pharmacology with a focus on the mechanisms underlying the development of drug tolerance. His scientific interests include: mechanisms of drug tolerance, behavioral pharmacology, patient compliance, learning and memory, regulatory behavior, tooth circulation, addictive disorders, pain (mechanisms and psychophysics).

  1. Ramsay, D.S., Kaiyala, K.J and Woods, S.C. Individual Differences in Biological Regulation: Predicting Vulnerability to Drug Addiction, Obesity, and Other Dysregulatory Disorders.  Experimental and Clinical Psychopharmacology, 28, 388–403, 2020. [doi:10.1037/pha0000371].
  2. Ramsay, D.S. and Woods, S.C. Physiological regulation: How it really works.  Cell Metabolism, 24, 361-364, 2016.
  3. Ramsay, D.S., Rothen, M., Scott, J., and Cunha-Cruz, J; on behalf of the Northwest PRECEDENT network.  Tooth wear and the role of salivary measures in general practice patients.  Clinical Oral Investigations, 19, 85-95, 2015.
  4. Ramsay, D.S., Al-Noori, S., Shao, J., Leroux, B.G. and Woods, S.C., Kaiyala, K.J. Predicting addictive vulnerability: Individual differences in initial responding to a drug’s pharmacological effects.  PLoS ONE, 10(4), e0124740-e0124740, 2015. [doi: 10.1371/journal.pone.0124740].
  5. Ramsay, D.S. and Woods, S.C.  Clarifying the roles of homeostasis and allostasis in physiological regulation.  Psychological Review, 121 , 225-247, 2014.
  6. Ramsay, D.S., Woods, S.C. and Kaiyala, K.J.  Repeated nitrous oxide exposure in rats causes a thermoregulatory sign-reversal with concurrent activation of opposing thermoregulatory effectors.  Temperature [Special Issue on Temperature and Toxicology with Focus on Drugs of Abuse], 1, 257-267, 2014.
  7. Ramsay, D.S., Woods, S.C. and Kaiyala, K.J.  Drug-induced regulatory overcompensation has motivational consequences: Implications for homeostatic and allostatic models of drug addiction.  Temperature [Special Issue on Temperature and Toxicology with Focus on Drugs of Abuse], 1, 248-256, 2014.
  8. Ramsay, D.S.  Patient compliance with oral hygiene regimens:  A behavioural self-regulation analysis with implications for technology.  International Dental Journal, 50, 304-311, 2000.
  9. Ramsay, D.S. and Woods, S.C.  Biological consequences of a drug administration:  Implications for acute and chronic tolerance.  Psychological Review, 104, 170-193, 1997.
  10. Ramsay, D.S., Årtun, J., and Martinen, S.S.  Reliability of pulpal blood flow measurements utilizing laser Doppler flowmetry.  Journal of Dental Research, 70, 1427-1430, 1991.

A complete list of Dr. Ramsay’s published work can be found in MyBibliography