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Background

• B.A. (High Honors), Philosophy and Psychology, University of California
• Ph.D., Psychology, (minor in Quantitative Studies), University of Washington
• Psychology Residency, Northwestern University Medical School

Research Interests

• Decision-making
• Behavior Change
• Psychometrics
• Dental Fear

Academic Activities

• Co-Director, Dentex 471 (Ethics)
• Member, Task Force on Professionalism and Ethics

Clinical Activities

• Psychological services, Dental Fears Research Clinic

Publications

1. Coolidge T, Irwin SP, Leyster KA, Milgrom P. (in press). Determinants of receiving intravenous sedation in a sample of dentally-fearful patients in the USA. SAAD Digest.
2. Coolidge T, Skaret E, Heima M, Johnson EK, Hillstead MB, Farjo N, Asmyhr A, Weinstein P. (2011). Thinking About Going to the Dentist: A Contemplation Ladder to assess dentally-avoidant individuals’ readiness to go to a dentist. BMC Oral Health, 11:4.
3. Arapostathis KN, Dabarakis NN, Coolidge T, Tsirlis A, Kotsanos N. (2010). Comparison of acceptance, preference and efficacy between jet injection INJEX and local infiltration anesthesia in 6-11 year old dental patients. Anesthesia Progress, 57, 3-12.
4. Coolidge T, Hillstead MB, Farjo N, Weinstein P, Coldwell SE. (2010). Additional psychometric data for the Spanish Modified Dental Anxiety Scale, and psychometric data for a Spanish version of the Revised Dental Beliefs Survey. BMC Oral Health,10:12.
5. Coolidge T, Heima M, Johnson EK, Weinstein P. (2009). The Dental Neglect Scale in Adolescents.BMC Oral Health 9:2.
6. Weinstein P, Coolidge T, Raff CA, Riedy CA. (2009). Recruiting rural dentally-avoidant adolescents into an intervention study. European Archives of Paediatric Dentistry, 10, 233-236.
7. Kotsanos N, Coolidge T, Velonis D, Arapostathis KN. (2009). A form of ‘parental presence/absence’ (PPA) technique for the child patient with dental behaviour management problems. European Archives of Paediatric Dentistry, 10, 90-92.
8. Coolidge T, Heaton LJ, Milgrom P. (2009). The challenge of sedation with adolescents: Case studies and clinical recommendations. SAAD Digest, 25, 29-36.
9. Heaton LJ, Coolidge T, Weinstein P. (2009). The Problem of Fear in Dentistry. In P. Milgrom P, Weinstein P, Heaton LJ., Treating Fearful Dental Patients: A Patient Management Handbook (3rd Ed.). Seattle: Dental Behavioral Resources, 5-34.
10. Arapostathis KN, Coolidge T, Emmanouil D, Kotsanos N. (2008). Reliability and validity of the Greek version of the Children’s Fear Survey Schedule – Dental Subscale (CFSS-DS). International Journal of Paediatric Dentistry, 18, 374-379.
11. Coolidge T, Chambers MA, Garcia LJ, Heaton LJ, Coldwell SE. (2008). Psychometric properties of Spanish-language adult dental fear measures. BMC Oral Health, 8: 15.
12. Coolidge T, Arapostathis KN, Emmanouil D, Dabarakis N, Patrikiou A, Economides N, Kotsanos N. (2008). Psychometric properties of the Greek versions of the Modified Corah Dental Anxiety Scale (MDAS) and the Dental Fear Survey (DFS). BMC Oral Health 8:29.
13. Pickrell JE, Heima M, Weinstein P, Coolidge T, Coldwell SE, Skaret E, Castillo J& Milgrom P. (2007) Using memory restructuring strategy to enhance dental behavior. International Journal of Paediatric Dentistry, 17, 439-448.
14. Coolidge T, Heima M, Coldwell SE, Weinstein P, Logan HL & Milgrom P. (2005). Reliability and validity of the Revised Iowa Dental Control Index in a Non-Clinical Sample. Personality and Individual Differences, 38, 773-783.
15. Coolidge T, Heima M, Coldwell SE, Weinstein P & Milgrom P. (2005). Psychometric properties of the Revised Dental Beliefs Survey. Community Dentistry and Oral Epidemiology, 33, 289-297.
16. Coolidge T, Heima M, Heaton LJ, Nakai Y, Höskuldsson Ó,  Smith TA, Weinstein P & Milgrom P. (2005). The Child Dental Control Assessment (CDCA) in youth: Reliability, validity and cross-cultural differences. European Journal of Paediatric Dentistry, 6, 35-43.
17. Nakai Y, Hirakawa T, Milgrom P, Coolidge T, Heima M, Mori Y, Ishihara C, Yakushiji N, Yoshida T & Shimono T. (2005). The Children’s Fear Survey Schedule – Dental Subscale in Japan.Community Dentistry and Oral Epidemiology, 33, 196-204.
18. Kotsanos N, Arhakis A, Coolidge T.  (2005). Parental presence vs. absence in the operatory: A technique to manage the uncooperative child dental patient. European Journal of Paediatric Dentistry, 6, 144-148.

Research Interests

Parkinson’s disease (PD), the most common serious movement disorder afflicting millions of Americans, is diagnosed when patients present with cardinal parkinsonian signs (bradykinesia, rigidity, tremor, and postural instability as depicted in the diagram on the left) and show a favorable responsiveness to levodopa or dopamine (DA) agonists.

Pathological hallmarks of PD are loss of dopaminergic neurons in the substantia nigra (SN) with resultant depletion of DA and the presence of Lewy bodies in the remaining neurons (indicated by an arrow in the photo micrograph). Despite decades of extensive research, there is currently still no cure for the disease, largely because its pathogenesis has not been fully understood yet. In addition, there are quite a few other movement disorders that mimic PD clinically including response to levodopa and DA agonists, making an accurate diagnosis of PD difficult sometimes even in the best hands. Finally, the natural course of PD varies substantially, with most patients developing first mild cognitive impairment (MCI) and then dementia as the disease progresses.

1) understand the molecular mechanisms of Parkinson’s disease development
2) understand the molecular mechanisms of Parkinson’s disease progression
3) explore unique biomarkers for diagnosing Parkinson’s disease and monitoring its progression

Research Laboratory

Publications

1. Montine, T. Shi, M, .and Zhang J (2010). Reduction in CSF amyloid b42 without a corresponding increase in tau species is commonly found in patients with Parkinson’s disease and cognitive impairment or dementia. Mov Disord In press (2010).
2. Mata, I., Zhang, j and Zabeitian C, A SNCA Variant Associated with Parkinson’s Disease and Plasma α-Synuclein Level. Arch Neurol In press (2010).
3. Shi M, Zabetian CP, Hancock AM, Ginghina C, Hong Z, Yearout D, Chung KA, Quinn JF, Peskind ER, Galasko D, Jankovic J, Leverenz JB, and Zhang J (2010). Significance and confounders of peripheral DJ-1 and alpha-synuclein in Parkinson’s disease. Neurosci Lett. 480:78–82, 2010.
4. Liu J, Shi M, Hong Z, Zhang J, Bradner J, Quinn T, Beyer RP, Mcgeer PL, Chen S, and Zhang J(2010). Identification of ciliary neurotrophic factor receptor alpha as a mediator of neurotoxicity induced by alpha-synuclein. Proteomics. 10(11):2138-50, 2010.
5. Rostomily RC, Born DE, Beyer RP, Jin J, Alvord EC Jr, Mikheev, AM, Matthews RT, Pan C, Khorasani L, Sonnen JA, Montine TJ, Shi M, and Zhang J (2010). Quantitative proteomic analysis of oligodendrogliomas with and without 1p/19q deletion. J Proteome Res. 7;9(5):2610-8, 2010.
6. Caudle WM, Bammler TK, Lin Y, Pan S, and Zhang J (2010). Using ‘omics’ to define pathogenesis and biomarkers of Parkinson’s disease. Expert Rev Neurother, 10(6):925-42, 2010.
7. Hong Z, Shi M, Chung KA, Quinn JF, Peskind ER, Galasko D, Jankovic J, Zabetian CP, Leverenz JB, Baird G, Montine TJ, Hancock AM, Hwang H, Pan C, Bradner J, Kang UJ, Jensen PH, and Zhang J(2010). DJ-1 and synuclein as biomarkers of Parkinson’s disease, Brain, 133:713-26, 2010.
8. Oh JH, Pan S, Zhang J, Gao J, MSQ: A tool for quantification of proteomics data generated by LC-MALDI TOF/TOF based targeted quantitative proteomics platform. Rapid Comm Mass Spec, 24(4):403-8, 2010.
9. Hwang H, Zhang JP, Chung KA, Leverenz JB, Zabetian CP, Peskind ER, Jankovic J, Su Z, Hancock AM, Pan C, Montine TJ, Pan S, Nutt J, Albin R, Gearing M, Beyer RP, Shi M, and Zhang J (2010). Glycoproteomics in Neurodegenerative Diseases. Mass Spec Reviews, 29(1):79-125.
10. Caudle WM, Zhang J (2009). Glutamate, excitotoxicity, and programmed cell death in Parkinson disease. Exp Neurol. 220:230-3, 2009.
11. Shi M, Bradner J, Bammler TK, Eaton DL, Zhang JP, Ye ZC, Wilson AM, Montine TJ, Pan C andZhang J (2009). Identification of synaptosomal glutathione S-transferase Pi as a key protein in Parkinson disease progression, Am J Pathol. 2009 Jun 4.
12. Caudle WM, Kitsou E, Li J, Bradner J, Zhang J (2009). A role for a novel protein, nucleolin, in Parkinson’s disease, Neurosci Lett. 2009 Jul 31;459(1):11-5. Epub 2009 May 4.
13. Liu J, Zhang JP, Shi M, Quinn T, Bradner J, Beyer R, Chen S, Zhang J (2009). Rab11a and HSP90 regulate recycling of extracellular alpha-synuclein. J Neurosci. 4;29(5):1480-5.
14. Pan S, Aebersold R, Chen R, Rush J, Goodlett DR, McIntosh MW, Zhang J, Brentnall TA (2009), Mass spectrometry based targeted protein quantification: methods and applications, J. Proteome Res. 6;8(2):787-797.

Interests

Our long-term goal is to identify means to ameliorate age-related muscle deterioration (sarcopenia) and combat muscle wasting in muscular dystrophy. Sarcopenia is characterized by a decline in mass, strength, and endurance of skeletal muscles, and by fat accumulation between and within myofibers. Subtle muscle injuries that occur during routine muscle activity raise a continuous demand for functional myofiber repair throughout life. However, myogenic stem cell performance declines in old age and this decline can be a contributory factor to sarcopenia. We investigate satellite cells, classically defined tissue specific myogenic stem cells that reside beneath the myofiber basal lamina, as well as non-myogenic progenitors associated with the microvasculature that may contribute to myogenesis by myogenic reprogramming. Our research approach is based on the view that muscle aging is not an isolated event that starts late in life, but rather a continuum of ongoing developmental biology processes that progress with life.

Publications

1. Keire P, Shearer A, Shefer G, Yablonka-Reuveni Z (2013) Isolation and culture of skeletal muscle myofibers as a means to analyze satellite cells. Methods Mol Biol. 946:431-468. Free public access in process. Pubmed
2. Stuelsatz P, Keire P, Almuly R, Yablonka-Reuveni Z (2012) A Contemporary Atlas of the Mouse Diaphragm: Myogenicity, Vascularity, and the Pax3 Connection. Journal of Histochemistry and Cytochemistry 60: 638-657. Free public access in process. Pubmed
3. Danoviz ME, Yablonka-Reuveni Z (2012) Skeletal muscle satellite cells: Background and methods for isolation and analysis in a primary culture system. Methods Mol Biol. 798: 21-52.Pubmed
4. Yablonka-Reuveni Z (2011) The skeletal muscle satellite cell: still young and fascinating at 50. Journal of Histochemistry and Cytochemistry 59: 1041-1059. Pubmed
5. Choi, SJ, Yablonka-Reuveni Z, Kaiyala KJ, Ogimoto K, Schwartz MW, Wisse BE (2011) Increased energy expenditure and leptin sensitivity account for low fat mass in myostatin deficient mice. Am J Physiol Endocrinol Metab. 300: E1031-1037.  Pubmed
6. Yablonka-Reuveni Z, Day K (2011) Skeletal muscle stem cells in the spotlight: the satellite cell. In: Regenerating the Heart: Stem Cells and the Cardiovascular System (“Stem Cell Biology and Regenerative Medicine Series”). Cohen I , Gaudette G, eds. Springer, Humana Press, Chapter 11, pp. 173-200.
7. Shefer G, Rauner G, Yablonka-Reuveni Z, Benayahu D (2010) Reduced satellite cell numbers and myogenic capacity in aging can be alleviated by endurance exercise. PLoS One. 2010 Oct 12;5(10):e13307 Pubmed

• PubMed Links

Interests

Research in the Totah lab is broadly centered on drug-endogenous substrate interactions. Cytochrome P450 enzymes are mainly known for their ability to metabolize xenobiotics. However, some isozymes are also involved in the metabolism of endogenous substrates such as retinoic acid, steroids and essential fatty acids. We are interested in studying the xenobiotics-endogenous substrate interaction and its potential for inducing tissue-specific toxicity in the kidney, heart, and lung. We are also involved in translational research and collaborate with colleagues in the medical center to bridge together wet-lab science and clinical science. On a daily basis we use molecular biology tools, LC-MS/MS analysis, kinetic analysis and chemical synthesis to understand the biochemical and functional aspects of various P450 enzymes.

A separate area of research focuses on cytochrome P450 BM3, and several mutants, as a model system to study the mechanism of electron transfer from NADPH to the heme and the catalytic mechanism of mammalian P450 enzymes.

Publications

1. Kaspera R, Naraharisetti SB, Tamraz B, Sahele T, Kwok P-Y, Marciante K, Heckbert SR, Psaty BM, Totah RA. “In Vitro Metabolism of Cerivastatin by CPY2C8 Variants Found in Patients Experiencing Rhabdomyolysis.” Pharmacogenetics and Genomics. In press.
2. Naraharisetti SB, Lin YS, Rieder M, Marciante K, Psaty BM, Thummel KE, Totah RA. “Human Liver Expression of CYP2C8: gender, age and genotype effects.” Drug Metab. Dispos. 38(6):889-93 (2010).
3. Lee C, Neul D, Clouser-Roche A, Dalvie D, Jiang J, Jones III JP, Wester M, Zientek M, Totah RA. “Identification of Novel Substrates for CYP2J2.” Drug Metab. Disp. 38:347-356 (manuscript featured on the cover of February 2010 edition).
4. Smith, H., Jones, JP III, Kalhorn, T., Farin, F., Stapleton, P., Davis, C., Perkins, J., Blough, D., Hebert M., Thummel, K., Totah, R.A. “Role of Cytochrome P450 2C8 and 2J2 genotype in calcineurin inhibitor induced chronic kidney disease.” Pharmacogenetics and Genomics. Nov;18(11):943-53 (2008).
5. Marciante, K., Totah, R.A., Heckbert, S., Smith, N., LeMaitre, R., Lumley, T., Rice, K., Hindorff, L., Bis, J., Hartman, B., Psaty, B, “Common Variation in Cytochrome P450 Epoxygenase Genes and the Risk of Incident Non-Fatal Myocardial Infarction and Ischemic Stroke.” Pharmacogenet Genomics Jun;18(6):535-543 (2008).
6. Totah, R.A., Sheffels, P., Roberts, T., Whittington, D., Thummel, K., Kharasch, ED. “Role of CYP2B6 in Stereoselective Human Methadone Metabolism.” Anesthesiology 108:363-74 (2008).
7. Totah, R.A., Allen, KE, Sheffels, P., Whittington, D., and Kharasch, E.D. “Enantiomeric metabolic interactions and stereoselective human methadone metabolism.” J Pharmacol Exp Ther. 321:389-399 (2007).
8. Gaedigk, A., Baker, D.W., Totah, R.A., Gaedigk, R., Pearce, R.E., Vyhlidal, C.A., Zeldin, D.C., and Leeder, J.S. “Variability of CYP2J2 expression in human fetal tissues.” J Pharmacol Exp Ther. 319:523-532 (2006).
9. Totah, R.A., Rettie, A.E. “Principles of drug metabolism, enzymes and tissues.” ComprehensiveDrug Metabolism, 2nd ed. Vol. 5 (2006).
10. Totah, R.A., Rettie, A.E. “CYP2C8: Substrates, Inhibitors, Pharmacogenetics and Clinical Relevance.” Clin Pharm Therap. 77: 341-352 (2005).
11. Hanzlik, R. P., Harriman, S. P., Shaffer, C. L., Koen, Y. M., Totah, R. A., and Cerny, M. A. “The Oxidative Metabolism of Cyclopropylamines: Fate of the Three Carbons and Other Interesting Observations.” Synthesis and Application of Isotopically Labelled Compounds, 8:111-114 (2004).
12. Huang, W., Lin, Y., McConn II, D., Calamia, J., Totah, R., Isoherranen, N., Glodowski, M., and Thummel, K. “Evidence of Significant Contribution From CYP3A5 to Hepatic Drug Metabolism.”Drug Met Dispos. 12:1434-1445 (2004).
13. Totah, R. A. and Hanzlik, R. P. “Oxidative and Non-Oxidative Decarboxylation of N-Alkyl-N-phenylglycines by Horseradish Peroxidase: Mechanistic Switching by Hydrogen Peroxide, Oxygen and Solvent Deuterium.” Biochemistry 43:7907-7914 (2004) .
14. Totah, R. A., and Hanzlik, R. P. “Non-Oxidative Decarboxylation of Glycine Derivatives by a Peroxidase.” J Am Chem Soc. 124:10000-10001 (2002).
15. Totah, R. A., and Hanzlik, R. P. “Detection of Aminium Ion Intermediates: N-Cyclopropyl versus N-Carboxymethyl Groups as Reporters.” J Am Chem Soc. 123:10107-10108 (2001).

Interests

Our research group is interested in elucidating the fundamental mechanisms of biomolecular recognition and applying the unique capabilities of biological molecules to biotechnologies. We would like to bridge the gap between understanding molecular structure-function relationships, and being able to utilize proteins/peptides/DNA for drug therapies, bioanalytics, diagnostics, and biomaterial development.

Publications

1. Drobny, G. P., Long, J. R., Karlsson, T., Shaw, W., Popham, J., Oyler, N., Bower, P., Stringer, J., Gregory, D., Mehta, M., and and Stayton, P. S. “Structural studies of biomaterials using double-quantum solid-state NMR Spectroscopy” (2003) Annual Reviews of Physical Chemistry, 54, 531-571.
2. Stayton, P. S., Shaw, W. J., Long, J. R., and Drobny, G. P. (2003) “Molecular Recognition at the Protein-HAP Interface” Critical Reviews in Oral Biology and Medicine, 14, 370-376.
3. Gilbert, M., Giachelli, C. M., and Stayton, P. S. (2003) “Biomimetic peptides that engage specific integrin-dependent signaling pathways and bind to calcium phosphate surfaces” J. Biomed. Mat. Res., 67, 69-77.
4. McDevitt, T. C., Woodhouse, K. A., Murry, C. E., Hauschka, S. D., and Stayton, P. S. (2003) “Spatially Organized Layers of Cardiomyocytes on Biodegradable Polyurethane Films for Myocardial Repair ” J. Biomed. Mat. Res. 66, 586-595.
5. Stayton PS. (2003) “Delivering the Vaccination Mail” Trends Biotechnol. 21, 465-467.
6. Malmstadt, N., Yager, P., Hoffman, A. S., and Stayton, P. S. (2003) “A Smart Microfluidic Affinity Chromatography Matrix Composed of Poly(N-isopropylacrylamide)-Coated Beads” Anal. Chem. (Accelerated Article) 75, 2943-2949.
7. Murthy, N., Campbell, J., Fausto, N., Hoffman, A. S., and Stayton, P. S. (2003) “Design and synthesis of pH-responsive polymeric carriers that target uptake and enhance the intracellular delivery of oligonucleotides. ” J. Cont. Rel., 89, 365-74.
8. Shimoboji, T., Larenas, E., Fowler, T., Kulkarni, S., Hoffman, A. S., and Stayton, P.S. (2002) “Photo-Responsive Polymer-Enzyme Switches” Proc. Natl. Acad. Sci. USA, 99, 16592-6.
9. McDevitt, T. C., Angello, J. C., Whitney, M. L., Reinecke, H., Hauschka, S. D., Murry, C. E., and Stayton, P. S. (2002) ” In vitro generation of differentiated cardiac myofibers on micropatterned laminin surfaces.” J. Biomed. Mat. Res. 60, 472-479.
10. Ding, Z., Fong, R. B., Long, C. J., Hoffman, A. S. and Stayton, P. S. (2001) “Size-dependent control of the binding of biotinylated proteins to streptavidin using a polymer shield” Nature 411, 59-62.

Research Interests

Skin cancer biology, particularly the molecular mechanism by which the protein kinase ATR mediates an essential cell cycle arrest following DNA damage such as by ultraviolet radiation.

A major portion of the lab is focused on basic, clinical and translational research aspects of Merkel cell carcinoma. We are involved in several clinical studies on this increasingly common and often lethal skin cancer to determine its basic genetic underpinnings as well as its clinical course and optimal management. The Merkel cell carcinoma Multicenter Interest Group (MMIG), an international collaborative group, has been formed to leverage diverse resources, interests and expertise to make a difference in this cancer.

• http://www.pnlab.org/
• http://merkelcell.org/

Publications

1. Boswell SA, Ongusaha PP, Nghiem P, Lee SW. The Protective Role of a Small GTPase RhoE Against UVB-induced DNA Damage in Keratinocytes. J Biol Chem. 282(7):4850-4858, 2007.
2. *Kawasumi M, Nghiem P.  Chemical genetics: Elucidating biological systems with small molecules.  J Invest Dermatol. 127(7):1577-84, 2007.
3. *Koo S-W, Hirakawa S, Fujii S, Kawasumi M, Nghiem P.  Protection from photodamage by topical application of caffeine after UV. Br J Dermatol. 156:957, 2007.
4. *Lu YP, Lou YR, Peng QY, Xie JG, Nghiem P, Conney AH. Effect of Caffeine on the ATR/Chk1 Pathway in the Epidermis of UVB-Irradiated Mice. Can Res. 68(7):2523-2529, 2008.
5. *Heffernan T, Kawasumi M, Blasina A, Anderes K, Conney A, Nghiem P.  ATR–Chk1 Pathway Inhibition Promotes Apoptosis after UV Treatment in Primary Human Keratinocytes: Potential Basis for the UV Protective Effects of Caffeine.  J Invest Dermatol. 2009.
6. * Lemos B, Storer B, Iyer J, Phillips JL, Bichakjian CK, Fang LC, Johnson TM, Liegeois-Kwon NJ, Otley CC, Paulson KG, Ross MI, Yu SS, Zeitouni NC, Byrd DR, Sondak VK, Gershenwald JE, Sober AJ, Nghiem P. Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: Analysis of 5,823 cases as the basis of the first consensus staging system for this cancer. J Am Acad Dermatol. 2010. [PubMed]
7. Kelly G. Paulson*, Joseph J. Carter*, Lisa G. Johnson, Kevin W. Cahill, Jayasri G. Iyer, David Schrama, Juergen C. Becker, Margaret M. Madeleine, Paul Nghiem**, Denise A.Galloway**. Antibodies to Merkel cell polyomavirus T-antigen oncoproteins reflect Merkel cell carcinoma tumor burden. Can Res. 2010. [PubMed]
8. Kelly G. Paulson, Jayasri G. Iyer, Paul Nghiem. Asymmetric lateral distribution of melanoma and Merkel cell carcinoma in the United States. J Am Acad Dermatol. 2011.

Interests

Current projects include:

• Identifying and applying biomimetic strategies to cell-substrate interactions important for promoting endothelial survival and angiogenesis particularly in the context of biomaterial healing,
• Biomolecular control of the foreign body reaction, with particular emphasis on the macrophage-mediated inflammatory response to biomaterials
• Mechanistic studies aimed at developing novel therapeutic targets and approaches for preventing ectopic calcification in disease and medical devices
• Cardiac valve and esophageal tissue engineering.

Publications

1. Rajachar R, Truong A, Giachelli CM. The influence of surface mineral and osteopontin on the formation and function of murine bone marrow macrophage derived osteoclasts, J Biomed Mater Res, J Mater Sci Mat med, 2008.
2. M. Linnes, B.D. Ratner, C.M. Giachelli. A Fibrinogen Based Precision Microporous Scaffold for Tissue Engineering: Development and Characterization. Biomaterials, 28(35):5298-306, 2007.
3. Beckstead, B.L. and C.M. Giachelli. “Mimicking cell-cell interactions at the biomaterial-cell interface” J Biomed Mater Res A. 2006 Oct; 79(1):94-103.
4. Li X, Ying-Yang H, Giachelli CM. Role of the Sodium Dependent Phosphate Cotransporter, Pit-1, in Vascular Smooth Muscle Calcification. Circ Res. 2006 98:905-12, 2006.
5. Tsai A, Rice J, Liaw L, Ratner B, Giachelli CM. Osteopntin reduces foreign body giant cell formation in response to biomaterial implantation. Biomaterials, 26:5835-43, 2005.
6. Ohri R, Tung E, Rajachar R, Giachelli CM. Mitigation of ectopic calcification in osteopontin-deficient mice by exogenous osteopontin: efficacy, potency and mechanism. Calcified Tissue Intl, 76:307-15, 2005.
7. Cuy JL, Beckstead BL, Brown CD, Hoffman AS, Giachelli CM. Adhesive protein interactions with chitosan: consequences for valve endothelial cell growth on tissue-engineering materials. J Biomed Mater Res, 67A: 538-547, 2003.
8. Wiester LM, Giachelli CM. Expression and function of the integrin, a9b1, in bovine aortic valve interstitial cells. J Heart Valve Disease, 12: 605-616, 2003.
9. Speer MY, McKee MD, Guldberg RE, Liaw L, Yang HY, Tung E, Karsenty G, Giachelli CM. Inactivation of the osteopontin gene enhances vascular calcification of matrix gla protein-deficient mice: evidence for osteopontin as an inducible inhibitor of vascular calcification in vivo. J Exp Med 196: 1047-1055, 2002.
10. Steitz SA, McKee MD, Liaw L, Giachelli CM. Osteopontin inhibits mineral deposition and promotes regression of ectopic calcification. Amer J Path 16:2035-2046, 2002.

Interests

We design and use microfluidic devices to better mimic the real microenvironment of nerve and cancer cells when we culture them outside of the organism. We are microfluidic!​​ ​Examples of questions that interest us are how neurons find their targets during development (axon guidance​), how they establish their connections (synaptogenesis​), and how we sense odors (olfaction​), among other projects. We also build microfluidic devices that allow us to personalize chemotherapy ​and devices to study cancer stem cells​​​. Laboratory website.

Publications

1. K.W. Moyes, C.G. Sip, W. Obenza, E. Yang, C. Horst, R.E. Welikson, S.D. Hauschka, A. Folch, and M. Laflamme, “Human embryonic stem cell-derived cardiomyocytes migrate in response to gradients of fibronectin and Wnt5a”, Stem Cells and Development 22, 1 (2013). Human embryonic stem cell-derived cardiomyocytes show robust promigratory responses to microfluidic gradients of fibronectin and Wnt5a.
2. Adina Scott, Anthony K. Au, Elise Vinckenbosch, and Albert Folch, “A microfluidic D-subminiature connector”, Lab on a Chip 13, 2036 (2013). We present a novel microfluidic connector based on standard electronic components that are available worldwide.
3. Peder Skafte-Pedersen, Christopher G. Sip, Albert Folch, and Martin Dufva, “Modular microfluidic systems using reversibly attached PDMS fluid control modules”, Journal of Micromech. Microeng. 23, 055011 (2013). We demonstrate the integration of PDMS-based fluid control modules with hard polymer chips made of PMMA.
4. Scott, A., Weir, K., Easton, C., Huynh, W., Moody, W.J., and Folch, A., “A microfluidic microelectrode array for simultaneous electrophysiology, chemical stimulation, and imaging of brain slices”, Lab Chip 13, 527 (2013). We demonstrate electrophysiological recordings from the surface of brain slices using a PDMS device featuring multiple apertures that function as extracellular electrodes as well as chemical stimulation points.
5. A. K. Au, H. Lai, B. R. Utela, and A. Folch, “Microvalves and Micropumps for BioMEMS”, Micromachines 2, 179 (2011). An in-depth review of the designs of micropumps and microvalves that have been used in the BioMEMS literature.
6. C. G. Sip, N. Bhattacharjee, and A. Folch, “A Modular Cell Culture Device for Generating Arrays of Gradients Using Stacked Microfluidic Flows”, Biomicrofluidics 5, 022210 (2011). This device reports a microfluidic gradient generator for cell culture applications based on the use of stacked laminar flows.
7. Hoyin Lai and Albert Folch, “Design and characterization of “single-stroke” peristaltic PDMS micropumps”, Lab Chip 11, 336 (2011). We demonstrate a new design of PDMS peristaltic pumps operated with a single control line.
8. Anna Boardman, Tim Chang, Albert Folch, and Norman J. Dovichi, “Indium-Tin Oxide Coated Microfabricated Device for the Injection of a Single Cell into a Fused Silica Capillary for Chemical Cytometry”, Analytical Chemistry 82, 9959 (2010). We describe a microfabricated device for the capture and injection of a single mammalian cell into a fused silica capillary for subsequent analysis by chemical cytometry.
9. Nirveek Bhattacharjee, Nianzhen Li, Thomas M. Keenan, and Albert Folch, “A neuron-benign microfluidic gradient generator for studying the response of mammalian neurons towards axon guidance factors”, Integrative Biology 2, 669 (2010). We record axonal growth of mouse embryonic cortical neurons in response to netrin gradients generated with a low-shear, open-bath microfluidic device.
10. David M. Cate, Christopher Sip, and Albert Folch, “A microfluidic platform for generation of sharp gradients in open-access culture”, Biomicrofluidics 4, 044105 (2010). We demonstrate a membrane-based gradient generator that is compatible with open cell cultures.
11. John M. Hoffman, Mitsuhiro Ebara, James J. Lai, Allan S. Hoffman, Albert Folch, and Patrick Stayton, “A helical flow, circular microreactor for separating and enriching “smart: polymer-antibody capture reagents”, Lab Chip 10, 3130 (2010). We report a mechanistic study of how flow and recirculation in a microreactor can be used to optimize the capture and release of stimuli-responsive polymer–protein reagents on stimuli-responsive polymer-grafted channel surfaces.
12. Ellen Tenstad, Anna Tourovskaia, Albert Folch, Ola Myklebost, and Edith Rian, “Extensive adipogenic and osteogenic differentiation of patterned human mesenchymal stem cells in a microfluidic device”, Lab Chip 10, 1401 (2010).–> Inside cover article.  Adipogenic and osteogenic differentiation of patterned human mesenchymal stem cells is demonstrated using long-term microfluidic perfusion.
13. Figueroa, X.A., Cooksey, G.A., Votaw, S.V., Horowitz, L.F., and Folch, A., “Large-scale investigation of the olfactory receptor space using a microfluidic microwell array”, Lab Chip 10, 1120 (2010). –> Cover article & Cited in Chemical Technology Highlights section. We show simultaneous calcium recordings of mouse dissociated olfactory sensory neurons in large microarrays so that the whole repertoire of mouse olfactory receptors is probed in one experiment.
14. Keenan, T.M., Frevert, C.W., Wu, A., Wong, V., and Folch, A., “A New Method for Studying Gradient-Induced Neutrophil Desensitization Based on an Open Microfluidic Chamber”, Lab Chip 10, 116 (2010). This paper demonstrates neutrophil chemotaxis measurements in an open microfluidic chamber.
15. Sidorova, J.M. Li, N., Schwartz, D.C., Folch, A., and Monnat Jr., R.J. “Microfluidic-assisted analysis of replicating DNA molecules”, Nature Protocols 4, 849 (2009). This paper presents detailed protocols on how to stretch DNA on glass surfaces using microfluidic channels.

Background

Michael L. Cunningham, MD, PhD, is chief of the Division of Craniofacial Medicine and professor of pediatrics at the University of Washington School of Medicine. He is the medical director of Seattle Children’s Craniofacial Center and holds the Jean Renny Endowed Chair in Craniofacial Medicine. He is also an adjunct professor of Biological Structures, Oral Biology, and Pediatrics Dentistry at the University of Washington Schools of Medicine and Dentistry. Dr. Cunningham balances responsibilities in administration, patient care and research. He does bedside teaching of medical students, dental students and pediatric residents. His clinical interests focus on the diagnosis and long-term interdisciplinary care of children with craniofacial malformations with a particular interest in craniosynostosis. He is co-investigator on several clinical research projects, ranging from the epidemiology of positional plagiocephaly to the risk factors for obstructive sleep apnea. Dr. Cunningham’s basic molecular and developmental biology lab has been active since 1993. Using mouse and human models Dr. Cunningham’s research team investigate the molecular causes of craniosynostosis and developmental pathogenesis of midface hypoplasia associated with syndromic craniosynostosis.

Publications

1. Speltz ML, Collett B, Stott-Miller M, Starr JR, Heike CL, Wolfram-Aduan A, King D, Cunningham ML. Case-control study of neurodevelopment in infants with deformational plagiocephaly.Pediatrics. 2010 Feb 15. [Epub ahead of print] PubMed PMID:20156894.
2. Hing AV, Click E, Vessey K, Seto M, Holder U, Gruss J, Hopper R, Cunningham ML. Bilateral lambdoid and sagittal synostosis (BLSS): a unique craniosynostosis syndrome or predictable phenotype? Am J Med Genet A 2009; 149A(5):1024-1032.
3. Ruiz-Correa S, Starr JR, Lin HJ, Kapp-Simon KA, Sze RW, Ellenbogen RG, Speltz ML, Cunningham ML. New severity indices for quantifying single-suture metopic craniosynostosis. Neurosurgery2008; 63(2):318-24; discussion 324-5.
4. Cunningham ML, Seto ML, Ratisoontorn C, Heike CL, Hing AV. Syndromic craniosynostosis: from history to hydrogen bonds. Orthod Craniofac Res (Invited review) 2007; 10:67–81.
5. Seto ML, Hing AV, Chang J, Hu M, Kapp-Simon KA, Patel PK, Burton BK, Kane A, Smyth MD, Hopper R, Ellenbogen RG, Stevenson K, Speltz ML, Cunningham ML. Isolated sagittal and coronal craniosynostosis associated with TWIST box mutations. Am J Med Genet A 2007; 143:678-686.
6. Hatch NE, Hudson M, Seto ML, Cunningham ML, Bothwell M. Intracellular retention, degradation, and signaling of glycosylation-deficient FGFR2 and craniosynostosis syndrome-associated FGFR2C278F. J Biol Chem 2006; 281(37):27292-27305.
7. Cunningham ML, Seto ML, Hing AV, Bull MJ, Hopkin RJ, Leppig KA. Cleidocranial dysplasia with severe parietal bone dysplasia: C-terminal RUNX2 mutations. Birth Defects Res A Clin Mol Teratol2006; 76(2):78-85.
8. Ratisoontorn C, Seto ML, Broughton KM, Cunningham ML. In-vitro differentiation profile of osteoblasts derived from patients with Saethre-Chotzen syndrome. Bone 2005; 36(4):627-634.
9. Heike CL, Seto M, Hing AV, Palidin A, Hu FZ, Preston RA, Ehrlich GD, Cunningham ML. A century of Jackson-Weiss syndrome: further definition of clinical and radiographic findings in ‘lost’ descendants of the original kindred. Am J Med Genet 2001; 100(4):315-324.
10. Dry GM, Yasinskaya YI, Williams JK, Erhlich G, Preston R, Gruss JS, Ellenbogen RG, Cunningham ML. Inhibition of apoptosis: a potential mechanism for syndromic craniosynostosis. Plast Reconstr Surg 2001; 107(2):425-432.

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

Current Research

• Dental Hygiene Education
• Community-based oral health promotion and program development
• Dental caries research
• International dental hygiene program development

Future Research

• Community-wide strategies to promote oral health
• Beta Defensins in caries prone children

Research Interests

Dr. Grembowski teaches social determinants of population health and health program evaluation, and his evaluation interests address prevention and the performance of health care systems. His studies have examined efforts to improve quality by increasing access to care in integrated delivery systems; managed care and physician referrals; managed care and patient-physician relationships; cost-effectiveness of preventive services for older adults; fluoridation effects on oral health and dental demand; financial incentives and dentist adoption of preventive technologies; effects of dental insurance on dental demand, and the link between mother and child access to dental care. His research interests include the design and performance of health care systems; prevention; technology diffusion. His methodology interests are program evaluation and survey research.

Publications

1. Lyles CR, Karter AJ, Young BA, Spigner C, Grembowski D, Schillinger D, Adler N. Patient-Reported Racial/Ethnic Healthcare Provider Discrimination and Medication Intensification in the Diabetes Study of Northern California (DISTANCE). J Gen Intern Med. 2011 May 6. [Epub ahead of print]  PMID: 21547610 PubMed
2. Bekemeier B, Grembowski D, Yang YR, Herting JR. Local Public Health Delivery of Maternal Child Health Services: Are Specific Activities Associated with Reductions in Black-White Mortality Disparities? Matern Child Health J. 2011 Apr 20. [Epub ahead of print]  PMID: 21505777 PubMed
3. Grembowski D, Bekemeier B, Conrad D, Kreuter W. Are local health department expenditures related to racial disparities in mortality? Soc Sci Med. 2010 Dec;71(12):2057-65. Epub 2010 Sep 29.  PMID: 21050631 PubMed
4. Grembowski D, Spiekerman C, Milgrom P. Linking mother access to dental care and child oral health. Community Dent Oral Epidemiol. 2009 Oct;37(5):381-90. Epub 2009 Jul 22.  PMID: 19681985 PubMed
5. Grembowski D, Spiekerman C, Milgrom P. Racial and ethnic differences in a regular source of dental care and the oral health, behaviors, beliefs and services of low-income mothers. Community Dent Health. 2009 Jun;26(2):69-76.  PMID: 19626737 PubMed