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Research Updates

A quick update on Penn Dental Medicine research with a snapshot of recent publications and research grant awards:


Recent Publications

Following is a selection of recent publications from Penn Dental Medicine standing faculty — those papers recently added to PubMed; those articles in which faculty were first/last authors include the abstract of the publication.

From the Dept. of Anatomy and Cell Biology:
Mesenchymal stem cell transplantation in tight-skin mice identifies miR-151-5p as a therapeutic target for systemic sclerosis..
Chen C, Wang D, Moshaverinia A, Liu D, Kou X, Yu W, Yang R, Sun L, Shi S.
Cell Res. 2017 Apr; 27(4):559-577. doi: 10.1038/cr.2017.11. Epub 2017 Jan 20.
Systemic sclerosis (SSc), an autoimmune disease, may cause significant osteopenia due to activation of the IL4Rα/mTOR pathway. Mesenchymal stem cell transplantation (MSCT) can ameliorate immune disorders in SSc via inducing immune tolerance. However, it is unknown whether MSCT rescues osteopenia phenotype in SSc. Here we show that MSCT can effectively ameliorate osteopenia in SSc mice by rescuing impaired lineage differentiation of the recipient bone marrow MSCs. Mechanistically, we show that donor MSCs transfer miR-151-5p to the recipient bone marrow MSCs in SSc mice to inhibit IL4Rα expression, thus downregulating mTOR pathway activation to enhance osteogenic differentiation and reduce adipogenic differentiation. Moreover, systemic delivery of miR-151-5p is capable of rescuing osteopenia, impaired bone marrow MSCs, tight skin, and immune disorders in SSc mice, suggesting that miR-151-5p may be a specific target for SSc treatment. Our finding identifies a previously unrecognized role of MSCT in transferring miRNAs to recipient stem cells to ameliorate osteopenia via rescuing a non-coding RNA pathway.

The P2X7 receptor links mechanical strain to cytokine IL-6 upregulation and release in neurons and astrocytes.
Lu W, Albalawi F, Beckel JM, Lim JC, Laties AM, Mitchell CH.
Curr Opin Chem Biol. 2017 Feb 21; 38:17-23. doi: 10.1016/j.cbpa.2017.02.007. [Epub ahead of print]
Mechanical strain in neural tissues can lead to the upregulation and release of multiple cytokines including IL-6. In the retina, the mechanosensitive release of ATP can autostimulate P2X7 receptors on both retinal ganglion cell neurons and optic nerve head astrocytes. Here we asked whether the purinergic signaling contributed to the IL-6 response to increased intraocular pressure (IOP) in vivo, and stretch or swelling in vitro.

From the Dept. of Biochemistry:
Expression and functional evaluation of biopharmaceuticals made in plant chloroplasts.
Zhang B, Shanmugaraj B, Daniell H.
Curr Opin Chem Biol. 2017 Feb 21; 38:17-23. doi: 10.1016/j.cbpa.2017.02.007. [Epub ahead of print]
After approval of the first plant-made biopharmaceutical by FDA for human use, many protein drugs are now in clinical development. Within the last decade, significant advances have been made in expression of heterologous complex/large proteins in chloroplasts of edible plants using codon optimized human or viral genes. Furthermore, advances in quantification enable determination of in-planta drug dosage. Oral delivery of plastid-made biopharmaceuticals (PMB) is affordable because it eliminates prohibitively expensive fermentation, purification processes addressing major challenges of short shelf-life after cold storage. In this review, we discuss recent advances in PMBs against metabolic, inherited or infectious diseases, and also mechanisms of post-translational modifications (PTM) in order to increase our understanding of functional PMBs.

Long-term evaluation of mucosal and systemic immunity and protection conferred by different polio booster vaccines..
Xiao Y, Daniell H.
Vaccine. 2017 Jan 19. pii: S0264-410X (16)31295-6. doi: 10.1016/j.vaccine.2016.12.061. [Epub ahead of print]
Oral polio vaccine (OPV) and Inactivated Polio Vaccine (IPV) have distinct advantages and limitations. IPV does not provide mucosal immunity and introduction of IPV to mitigate consequences of circulating vaccine-derived polio virus from OPV has very limited effect on transmission and OPV campaigns are essential for interrupting wild polio virus transmission, even in developed countries with a high coverage of IPV and protected sewer systems. The problem is magnified in many countries with limited resources. Requirement of refrigeration for storage and transportation for both IPV and OPV is also a major challenge in developing countries. Therefore, we present here long-term studies on comparison of a plant-based booster vaccine, which is free of virus and cold chain with IPV boosters and provide data on mucosal and systemic immunity and protection conferred by neutralizing antibodies. Mice were primed subcutaneously with IPV and boosted orally with lyophilized plant cells containing 1μg or 25μg polio viral protein 1 (VP1), once a month for three months or a single booster one year after the first prime. Our results show that VP1-IgG1 titers in single or double dose IPV dropped to background levels after one year of immunization. This decrease correlated with >50% reduction in seropositivity in double dose and 10% seropositivity in single dose IPV against serotype 1. Single dose IPV offered no or minimal protection against serotype 1 and 2 but conferred protection against serotype 3. VP1-IgA titers were negligible in IPV single or double dose vaccinated mice. VP1 antigen with two plant-derived adjuvants induced significantly high level and long lasting VP1-IgG1, IgA and neutralizing antibody titers (average 4.3-6.8 log2 titers). Plant boosters with VP1 and plant derived adjuvants maintained the same level titers from 29 to 400days and conferred the same level of protection against all three serotypes throughout the duration of this study. Even during period, when no plant booster was given (∼260days), VP1-IgG1 titers were maintained at high levels. Lyophilized plant cells expressing VP1 can be stored without losing efficacy, eliminating cold chain. Virus-free, cold-chain free vaccine is ready for further clinical development.

Oral Tolerance Induction in Hemophilia B Dogs Fed with Transplastomic Lettuce.
Herzog RW, Nichols TC, Su J, Zhang B, Sherman A, Merricks EP, Raymer R, Perrin GQ, Häger M, Wiinberg B, Daniell H.
Mol Ther. 2017 Feb 1; 25(2):512-522. doi: 10.1016/j.ymthe.2016.11.009.
Anti-drug antibodies in hemophilia patients substantially complicate treatment. Their elimination through immune tolerance induction (ITI) protocols poses enormous costs, and ITI is often ineffective for factor IX (FIX) inhibitors. Moreover, there is no prophylactic ITI protocol to prevent anti-drug antibody (ADA) formation. Using general immune suppression is problematic. To address this urgent unmet medical need, we delivered antigen bioencapsulated in plant cells to hemophilia B dogs. Commercial-scale production of CTB-FIX fusion expressed in lettuce chloroplasts was done in a hydroponic facility. CTB-FIX (∼1 mg/g) in lyophilized cells was stable with proper folding, disulfide bonds, and pentamer assembly after 30-month storage at ambient temperature. Robust suppression of immunoglobulin G (IgG)/inhibitor and IgE formation against intravenous FIX was observed in three of four hemophilia B dogs fed with lyophilized lettuce cells expressing CTB-FIX. No side effects were detected after feeding CTB-FIX-lyophilized plant cells for >300 days. Coagulation times were markedly shortened by intravenous FIX in orally tolerized treated dogs, in contrast to control dogs that formed high-titer antibodies to FIX. Commercial-scale production, stability, prolonged storage of lyophilized cells, and efficacy in tolerance induction in a large, non-rodent model of human disease offer a novel concept for oral tolerance and low-cost production and delivery of biopharmaceuticals.

Phagocytosis Dependent Ketogenesis in Retinal Pigment Epithelium.
Reyes-Reveles J, Dhingra A, Alexander D, Bragin A, Philp NJ, Boesze-Battaglia K.
J Biol Chem. 2017 Mar 16. pii: jbc.M116.770784. doi: 10.1074/jbc.M116.770784. [Epub ahead of print]
Daily, the retinal pigment epithelium (RPE) ingests a bolus of lipid and protein in the form of phagocytized photoreceptor outer segments (OS). The RPE like the liver expresses enzymes required for fatty acid oxidation (FAO) and ketogenesis. This suggests that these pathways play a role in the disposal of lipids from ingested OS as well as providing a mechanism for recycling metabolic intermediates back to the outer retina. In this study, we examined whether OS phagocytosis was linked to ketogenesis. We found increased levels of β-hydroxy-butyrate (β-HB) in the apical media following ingestion of OS by human fetal RPE and ARPE19 cells cultured on transwell inserts. No increase in ketogenesis was observed following ingestion of oxidized OS or latex beads. Our studies further defined the connection between OS phagocytosis and ketogenesis in wild type mice and mice with defects in phagosome maturation using a mouse RPE explant model. In explant studies, the levels of β-HB released were temporally correlated with OS phagocytic burst after light onset. In the Mreg-/- mouse where phagosome maturation is delayed, there was a temporal shift in the release of β-HB. An even more pronounced shift in maximal β-HB production was observed in the Abca4-/- RPE, in which loss of the ATP-binding cassette A4 (ABCA4) transporter results in defective phagosome processing and accumulation of lipid debris. These studies suggest that FAO and ketogenesis are key to supporting the metabolism of the RPE and preventing the accumulation of lipids that lead to oxidative stress and mitochondrial dysfunction.

Bestrophinopathy: An RPE-photoreceptor interface disease.
Guziewicz KE, Sinha D, Gómez NM, Zorych K, Dutrow EV, Dhingra A, Mullins RF, Stone EM, Gamm DM, Boesze-Battaglia K, Aguirre GD.
Prog Retin Eye Res. 2017 Jan 19. pii: S1350-9462(16)30086-6. doi: 10.1016/j.preteyeres.2017.01.005. [Epub ahead of print]

PBJ is now a leading open access plant journal.
Daniell H.
Plant Biotechnol J. 2017 Jan;15(1):3. doi: 10.1111/pbi.12687.

Plant-based vaccines for oral delivery of type 1 diabetes-related autoantigens: Evaluating oral tolerance mechanisms and disease prevention in NOD mice.
Posgai AL, Wasserfall CH, Kwon KC, Daniell H, Schatz DA, Atkinson MA.
Sci Rep. 2017 Feb 13;7:42372. doi: 10.1038/srep42372.

From the Dept. of Endodontics:
A Survey of Cone-beam Computed Tomographic Use among Endodontic Practitioners in the United States.
Setzer FC, Hinckley N, Kohli MR, Karabucak B.
J Endod. 2017 Mar 11. pii: S0099-2399(16)31067-6. doi: 10.1016/j.joen.2016.12.021. [Epub ahead of print]
Cone-beam computed tomographic (CBCT) imaging is an emerging technology for clinical endodontic practice. The aim of this study was to investigate the acceptance, accessibility, and usage of CBCT imaging among American Association of Endodontists members in the United States by means of an online survey. There is a widespread application of CBCT technology in endodontic practice; however, results from the survey also confirmed that the benefit versus risk ratio should always be in favor of the patient if CBCT scans are taken.

From the Dept. of Microbiology:
MFG-E8 inhibits periodontitis in non-human primates and its gingival crevicular fluid levels can differentiate periodontal health from disease in humans..
Kajikawa T, Meshikhes F, Maekawa T, Hajishengallis E, Hosur KB, Abe T, Moss K, Chavakis T, Hajishengallis G.
J Clin Periodontol. 2017 Feb 16. doi: 10.1111/jcpe.12707. [Epub ahead of print]
We have previously shown that the secreted glycoprotein MFG-E8 has anti-inflammatory and anti-osteoclastogenic properties. Our objective was to investigate the potential of MFG-E8 as a diagnostic or therapeutic agent in periodontitis. In NHPs, sites treated with MFG-E8-Fc exhibited significantly less ligature-induced periodontal inflammation and bone loss than Fc control-treated sites. In humans, the GCF levels of MFG-E8 were significantly higher in health than in periodontitis, whereas the reverse was true for the proinflammatory cytokines tested. Consistently, MFG-E8 was elevated in GCF after both non-surgical (SRP) and surgical periodontal treatment of periodontitis patients. MFG-E8 is, in principle, a novel therapeutic agent and biomarker of periodontitis.

Dendritic cell-mediated mechanisms triggered by LT-IIa-B₅, a mucosal adjuvant derived from a type II heat-labile enterotoxin of Escherichia coli.
Lee CH, Hajishengallis G, Connell TD.

Expression and Regulation of Cholecystokinin Receptor in the Chicken’s Immune Organs and Cells.
El-Kassas S, Odemuyiwa S, Hajishengallis G, Connell TD, Nashar TO.
J Clin Cell Immunol. 2016 Dec;7(6). pii: 471. doi: 10.4172/2155-9899.1000471. Epub 2016 Nov 25.

From leukocyte recruitment to resolution of inflammation: the cardinal role of integrins.
Kourtzelis I, Mitroulis I, von Renesse J, Hajishengallis G, Chavakis T.
J Leukoc Biol. 2017 Mar 14. pii: jlb.3MR0117-024R. doi: 10.1189/jlb.3MR0117-024R. [Epub ahead of print]

Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1.
Moutsopoulos NM, Zerbe CS, Wild T, Dutzan N, Brenchley L, DiPasquale G, Uzel G, Axelrod KC, Lisco A, Notarangelo LD, Hajishengallis G, Notarangelo LD, Holland SM.
N Engl J Med. 2017 Mar 23;376(12):1141-1146. doi: 10.1056/NEJMoa1612197

Prophylactic Herpes Simplex Virus 2 (HSV-2) Vaccines Adjuvanted with Stable Emulsion and Toll-Like Receptor 9 Agonist Induce a Robust HSV-2-Specific Cell-Mediated Immune Response, Protect against Symptomatic Disease, and Reduce the Latent Viral Reservoir
Hensel MT, Marshall JD, Dorwart MR, Heeke DS, Rao E, Tummala P, Yu L, Cohen GH, Eisenberg RJ, Sloan DD.
J Virol. 2017 Feb 22. pii: JVI.02257-16. doi: 10.1128/JVI.02257-16. [Epub ahead of print]

From the Dept. of Oral Surgery/Pharmacology:
Phase Four, Randomized, Double-Blinded, Controlled Trial of Phentolamine Mesylate in Two- to Five-year-old Dental Patients..
Hersh EV, Lindemeyer R, Berg JH, Casamassimo PS, Chin J, Marberger A, Lin BP, Hutcheson MC, Moore PA, Group PS.
Pediatr Dent. 2017 Jan 15;39(1):39-45.
The purpose of this study was to evaluate, using a randomized, double-blind methodology: (1) the safety of phentolamine mesylate (Oraverse) in accelerating the recovery of soft tissue anesthesia following the injection of two percent lidocaine plus 1:100,000 epinephrine in two- to five-year-olds; and (2) efficacy in four- to five-year-olds only. Phentolamine was well tolerated and safe in three- to five-year-olds; in four- to five-year-olds, a statistically significant more rapid recovery of lip sensation compared to sham injections was determined.

Vaginoplasty with an Autologous Buccal Mucosa Fenestrated Graft in Two Patients with Vaginal Agenesis: A Multidisciplinary Approach and Literature Review.
Chan JL, Levin PJ, Ford BP, Stanton DC, Pfeifer SM.
J Minim Invasive Gynecol. 2017 Feb 15. pii: S1553-4650(17)30133-4. doi: 10.1016/j.jmig.2016.12.030. [Epub ahead of print]

Neural Progenitor-Like Cells Induced from Human Gingiva-Derived Mesenchymal Stem Cells Regulate Myelination of Schwann Cells in Rat Sciatic Nerve Regeneration.
Zhang Q, Nguyen P, Xu Q, Park W, Lee S, Furuhashi A, Le AD.
Stem Cells Transl Med. 2017 Feb;6(2):458-470. doi: 10.5966/sctm.2016-0177. Epub 2016 Sep 7.
Regeneration of peripheral nerve injury remains a major clinical challenge. Recently, mesenchymal stem cells (MSCs) have been considered as potential candidates for peripheral nerve regeneration; however, the underlying mechanisms remain elusive. Here, we show that human gingiva-derived MSCs (GMSCs) could be directly induced into multipotent NPCs (iNPCs) under minimally manipulated conditions without the introduction of exogenous genes. Using a crush-injury model of rat sciatic nerve, we demonstrate that GMSCs transplanted to the injury site could differentiate into neuronal cells, whereas iNPCs could differentiate into both neuronal and Schwann cells. After crush injury, iNPCs, compared with GMSCs, displayed superior therapeutic effects on axonal regeneration at both the injury site and the distal segment of the injured sciatic nerve. Mechanistically, transplantation of GMSCs, especially iNPCs, significantly attenuated injury-triggered increase in the expression of c-Jun, a transcription factor that functions as a major negative regulator of myelination and plays a central role in dedifferentiation/reprogramming of Schwann cells into a progenitor-like state. Meanwhile, our results also demonstrate that transplantation of GMSCs and iNPCs consistently increased the expression of Krox-20/EGR2, a transcription factor that governs the expression of myelin proteins and facilitates myelination. Altogether, our findings suggest that transplantation of GMSCs and iNPCs promotes peripheral nerve repair/regeneration, possibly by promoting remyelination of Schwann cells mediated via the regulation of the antagonistic myelination regulators, c-Jun and Krox-20/EGR2.

From the Dept. of Orthodontics & Divs. of Pediatric Dentistry & Community Oral Health:
Candida albicans stimulates Streptococcus mutans microcolony development via cross-kingdom biofilm-derived metabolites.
Kim D, Sengupta A, Niepa TH, Lee BH, Weljie A, Freitas-Blanco VS, Murata RM, Stebe KJ, Lee D, Koo H.
Sci Rep. 2017 Jan 30;7:41332. doi: 10.1038/srep41332
Candida albicans is frequently detected with heavy infection of Streptococcus mutans in plaque-biofilms from children affected with early-childhood caries, a prevalent and costly oral disease. The presence of C. albicans enhances S. mutans growth within biofilms, yet the chemical interactions associated with bacterial accumulation remain unclear. Thus, this study was conducted to investigate how microbial products from this cross-kingdom association modulate S. mutans build-up in biofilms. Our data revealed that bacterial-fungal derived conditioned medium (BF-CM) significantly increased the growth of S. mutans and altered biofilm 3D-architecture in a dose-dependent manner, resulting in enlarged and densely packed bacterial cell-clusters (microcolonies). Intriguingly, BF-CM induced S. mutans gtfBC expression (responsible for Gtf exoenzymes production), enhancing Gtf activity essential for microcolony development. Using a recently developed nanoculture system, the data demonstrated simultaneous microcolony growth and gtfB activation in situ by BF-CM. Further metabolites/chromatographic analyses of BF-CM revealed elevated amounts of formate and the presence of Candida-derived farnesol, which is commonly known to exhibit antibacterial activity. Unexpectedly, at the levels detected (25-50 μM), farnesol enhanced S. mutans-biofilm cell growth, microcolony development, and Gtf activity akin to BF-CM bioactivity. Altogether, the data provide new insights on how extracellular microbial products from cross-kingdom interactions stimulate the accumulation of a bacterial pathogen within biofilms.

From the Dept. of Periodontics:
Esthetic Crown Lengthening : Contemporary Guidelines for Achieving Ideal Gingival Architecture and Stability.
Lee E
Curr Oral Health Rep. DOI 10.1007/s40496-017-0141-4
The achievement and maintenance of ideal gingival margin levels and architecture constitute essential requirements for esthetic crown lengthening procedures. The use of a scalpel blade and ancillary mechanical armamentarium to sculpt the gingival margins may not be the most efficient or accurate surgical method available, and this review will consider the use of contemporary alternatives. Additionally, the fact that gingival margin levels are often not stable following esthetic crown lengthening surgery is a phenomenon that has perplexed clinicians. The purpose of this article is to review the pertinent literature in search of predictable clinical protocols for esthetic crown lengthening.

FOXO1 expression in keratinocytes promotes connective tissue healing..
Zhang C, Lim J, Liu J, Ponugoti B, Alsadun S, Tian C, Vafa R, Graves DT.
Sci Rep. 2017 Feb 21;7:42834. doi: 10.1038/srep42834.
Wound healing is complex and highly orchestrated. It is well appreciated that leukocytes, particularly macrophages, are essential for inducing the formation of new connective tissue, which requires the generation of signals that stimulate mesenchymal stem cells (MSC), myofibroblasts and fibroblasts. A key role for keratinocytes in this complex process has yet to be established. To this end, we investigated possible involvement of keratinocytes in connective tissue healing. By lineage-specific deletion of the forkhead box-O 1 (FOXO1) transcription factor, we demonstrate for the first time that keratinocytes regulate proliferation of fibroblasts and MSCs, formation of myofibroblasts and production of collagen matrix in wound healing. This stimulation is mediated by a FOXO1 induced TGFβ1/CTGF axis. The results provide direct evidence that epithelial cells play a key role in stimulating connective tissue healing through a FOXO1-dependent mechanism. Thus, FOXO1 and keratinocytes may be an important therapeutic target where healing is deficient or compromised by a fibrotic outcome.

Subperiosteal Minimally Invasive Aesthetic Ridge Augmentation Technique (SMART): A New Standard for Bone Reconstruction of the Jaws..
Lee EA.
Int J Periodontics Restorative Dent. 2017 Mar/Apr;37(2):165-173. doi: 10.11607/prd.3171.
Traditional guided bone regeneration techniques include flap mobilization and placement of a bone graft, often with the use of space-maintaining devices and cell-occlusive membranes. This approach is associated with frequent complications that negatively affect the outcome of the augmentation and the peri-implant soft tissue esthetics. Although current tunneling techniques have focused on periodontal soft tissue applications, earlier publications described their use for horizontal augmentation of mandibular posterior edentulous ridges in full-denture patients. More recently, the use of recombinant human platelet-derived growth factor (rhPDGF-BB) was tested with different bone matrices to treat maxillary anterior edentulous spans. The present case series reports the use of a subperiosteal minimally invasive aesthetic ridge augmentation technique (SMART) to treat 60 single and multiple edentulous, dentate, and implant sites on 21 patients and five treatment categories with a follow-up period ranging from 4 to 30 months. The technique includes the use of a laparoscopic approach to deliver a growth factor/xenograft combination into a subperiosteal pouch. No flap elevation, cell-occlusive membranes, space-maintaining devices, or decortication procedures were used. The results from this case series demonstrated predictable and consistent bone regeneration. The average gain in ridge width for all treatment categories was 5.11 mm (SD 0.76 mm), which compares favorably with previously published reports. Morbidity and complication rates were consistently reduced as well. Human histology results show xenograft particles surrounded by newly formed bone. The role of the periosteum as a source of pluripotent cells in growth factor–mediated bone regeneration is discussed.

TNFα contributes to diabetes impaired angiogenesis in fracture healing.
Lim JC, Ko KI, Mattos M, Fang M, Zhang C, Feinberg D, Sindi H, Li S, Alblowi J, Kayal RA, Einhorn TA, Gerstenfeld LC, Graves DT.
Bone. 2017 Mar 8;99:26-38. doi: 10.1016/j.bone.2017.02.014. [Epub ahead of print]
Diabetes increases the likelihood of fracture, interferes with fracture healing and impairs angiogenesis. The latter may be significant due to the critical nature of angiogenesis in fracture healing. Although it is known that diabetes interferes with angiogenesis the mechanisms remain poorly defined. We examined fracture healing in normoglycemic and streptozotocin-induced diabetic mice and quantified the degree of angiogenesis with antibodies to three different vascular markers, CD34, CD31 and Factor VIII. The role of diabetes-enhanced inflammation was investigated by treatment of the TNFα-specific inhibitor, pegsunercept starting 10days after induction of fractures. Diabetes decreased both angiogenesis and VEGFA expression by chondrocytes. The reduced angiogenesis and VEGFA expression in diabetic fractures was rescued by specific inhibition of TNF in vivo. In addition, the TNF inhibitor rescued the negative effect of diabetes on endothelial cell proliferation and endothelial cell apoptosis. The effect of TNFα in vitro was enhanced by high glucose and an advanced glycation end product to impair microvascular endothelial cell proliferation and tube formation and to stimulate apoptosis. The effect of TNF, high glucose and an AGE was mediated by the transcription factor FOXO1, which increased expression of p21 and caspase-3. These studies indicate that inflammation plays a major role in diabetes-impaired angiogenesis in endochondral bone formation through its effect on microvascular endothelial cells and FOXO1.

Subgingival microbiota dysbiosis in systemic lupus erythematosus: association with periodontal status.
Corrêa JD, Calderaro DC, Ferreira GA, Mendonça SM, Fernandes GR, Xiao E, Teixeira AL, Leys EJ, Graves DT, Silva TA.
Microbiome. 2017 Mar 20;5(1):34. doi: 10.1186/s40168-017-0252-z.

From the Division of Community Oral Health:
An Assessment of Global Oral Health Education in U.S. Dental Schools.
Sung J, Gluch JI.
J Dent Educ. 2017 Feb;81(2):127-134.
Dental schools need to produce graduates who are adequately prepared to respond to the complex needs and challenges of the increasingly diverse and interconnected world in which they will practice dentistry. To enhance discussions about the coverage of global oral health competencies in dental education, the aims of this study were to assess how global health education is currently incorporated into predoctoral dental training in the U.S. and which global oral health competencies are being covered. Surveys were emailed to all 64 accredited U.S. dental schools during the 2015-16 academic year. Respondents from 52 schools completed the survey (response rate 81%). The results showed that social determinants of oral diseases and conditions, how to identify barriers to use of oral health services, and how to work with patients who have limited dental health literacy were covered in the greatest number of responding schools’ curricula. Key areas of global health curricula that were covered rarely included global dental infrastructure, data collection design, and horizontal and vertical programming approaches to health improvement. Despite current dialogue on the addition of global oral health competencies to dental curricula, only 41% of the responding schools were currently planning to expand their global oral health education. Based on these results, the authors conclude that it may be most feasible for dental schools to add recommended global oral health competencies to their curricula by incorporating didactic content into already established courses.

(Please Note: Due to the variable nature of when publishers index articles to PubMed, there may be some articles that have come out recently that do not yet appear in the PubMed database, and given the variable nature of when publishers index articles to PubMed, some older articles may only have been added to PubMed recently.)

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Recent Grant Awards

Department of Anatomy & Cell Biology
Approaches to Enhance Lysosomal Function in RPE Cells
Chloroquine retinopathy can lead to the loss of vision in patients, with numbers rising as the use of chloroquine increases. While the drug is known to target the lysosomes of RPE cells, it is unclear how this leads to pathology. This proposal will determine whether novel functions of RPE lysosomes like calcium signaling and secretion are impaired by chloroquine and evaluate the ability of treatments to reduce the damage.
Funding Source: NIH
Principal Investigator: Dr. Claire Mitchell, Associate Professor

FAS Controls Exosome-Mediated miRNA Transfer in MSC-Based Therapy
The craniofacial region is involved in a majority of systemic sclerosis patients, who are identified to associate with bone resorption and fractures as a common clinical feature. the findings of this proposal will better reveal the pathophysiology of systemic sclerosis to provide an efficient stem cell therapy for disease management.
Funding Source: NIH
Principal Investigator: Dr. Chi-Der Chen, Postdoctoral Research, Shi Lab

Department of Biochemistry
Control of Pathogenic Microbes through Disruption of Oral Biofilms Using Therapeutic Proteins Produced in Edible Plant Chloroplasts
This initial research exploration will provide proof of concept that Dr. Henry Daniell’s plant-based, biofilm degrading enzymes will augment the performance of known antimicrobial compounds (eg. essential oils) in Dr. Michel Koo’s in vitro biofilm models.
Funding Source: Johnson & Johnson
Principal Investigator: Dr. Henry Daniell, Professor and Interim Chair

Department of Microbiology
High-throughput SPR for Screening and Characterizing Vaccines
For this Direct-to-Phase II SBIR, Wasatch proposes to capitalize upon Dr. Cohen’s strong preliminary results by building a custom Surface Plasmon Resonance (SPR) sensor for vaccine research that injects 96 samples simultaneously and incorporates an array detector with 384 sensing locations—all while maintaining the data quality and operating protocols of current SPR systems.
Funding Source: Wasatch Microfluidics, NIH
Principal Investigator: Dr. Gary Cohen, Professor

Predicting Epitopes in Vaccine and Therapeutic Antibody Research
A thorough knowledge of the immune response generated in the herpes infected human is key to development of a rational vaccine candidate. Detailed characterization of antigen binding is fundamental to understanding and potentially improving mechanisms of action of vaccines. To support such characterization for large panels of herpes-related antibodies and antigen variant proteins, computational design and analysis methods will be integrated with a high-throughput multiplexed experimental platforms. By enabling a rich analysis at much higher throughput than traditional structural studies, this approach promises to better drive discovery and development of herpes vaccines and therapeutic antibodies.
Funding Source: Wasatch Microfluidics, NIH
Principal Investigator: Dr. Gary Cohen, Professor

Local Endogenous Regulators of Functional Immune Plasticity in the Periodontium
Periodontitis is a prevalent disease causing destruction of the tooth-supporting tissues and may adversely affect systemic health. Preliminary studies indicate that a protein expressed by periodontal tissue resident cells, designated Del-1, acts as a gatekeeper of inflammation. This project investigates the hypothesis that Del-1 additionally promotes resolution of inflammation and restores tissue integrity, thereby paving the way to a new class of endogenous therapeutic molecules for treating periodontitis.
Funding Source: NIH
Principal Investigator: Dr. George Hajishengallis, Thomas W. Evans Centennial Professor

Neutrophil Homeostasis and Periodontitis: Novel Concepts and Treatments
Leukocyte adhesion deficiency Type I (LAD-I) leads to destruction of periodontal bone and premature loss of primary and permanent teeth, and has therefore serious adverse psychological and functional consequences in children. The underlying etiology has been historically attributed to impaired neutrophil surveillance of the periodontal infection, although this form of periodontitis has proven unresponsive to antibiotics and/or mechanical removal of the tooth-associated biofilm. This project investigates the hypothesis that LAD-I–associated periodontitis is driven by the disruption of a key neutrophil homeostatic mechanism that leads to overproduction of a potent bone-resorptive cytokine (interleukin 17) and proposes novel treatments that can block this destructive process.
Funding Source: NIH
Principal Investigator: Dr. George Hajishengallis, Thomas W. Evans Centennial Professor

Department of Oral Surgery/Pharmacology
Defining mechanical injury, hypoxia, and disease progression in TMJ Osteoarthritis and Pain
Disorders of the temporomandibular joint (TMJ) are very common, with over 70% of the population reporting signs or symptoms. Most patients experience a self-limited disease course that is managed with physical therapy and/or NSAIDS. Yet, 15% of the TMJ disorder (TMD) cases present as an aggressive disease recalcitrant to therapies, and lead to the development of chronic centralized pain, making TMDs the second most common musculoskeletal condition.
Funding Source: Oral and Maxillofacial Surgery Foundation
Principal Investigator: Granquist, Eric

A Double-Blind, Partial Cross-Over, Incomplete Factorial Study to Assess the Local Anesthetic Efficacy and Safety of CTY-5339 Anesthetic Spray when Applied to the Cheek Mucosal Tissue in Normal Volunteers
This study will assess the safety and efficacy of an anesthetic spray using ECGs and methemoglobinemia (blood co-oximetry).
Funding Source: Cetylite
Principal Investigator: Dr. Elliot Hersh, Professor

Penn Multidisciplinary Consortium: Personalized Dental, Oral and Craniofacial Tissue Regeneration
In the present study, we will delineate the role of stromal cell-derived IL-6 in the regulation of EMT process and acquisition of stem-like cell properties in ameloblastoma epithelial cells and the underlying signaling mechanisms.
Funding Source: Oral and Maxillofacial Surgery Foundation
Principal Investigator: Dr. Qunzhou Zhang, Senior Research Investigator

Department of Orthodontics
A Novel Anti-Caries Approach to Modulate Virulence of Cariogenic Biofilms
Dr. Koo’s lab has developed a potent new anti-caries approach by combining food-derived antibiofilm agents and fluoride with nanotechnology. Nanoparticle carriers (NPC) can maximize drug efficacy via enhanced retention and pH-activated release of therapeutic agents at the tooth/biofilm interface. Furthermore, NPC can encapsulate the bioactive agents to make them water-soluble, critical to practical formulation development. The low-cost and flexibility of NPC chemistry allows further optimization as well as utilization in a variety of applications (from mouthrinses/toothpaste to dental materials.
Funding Source: NIH
Principal Investigator: Dr. Michel Koo, Professor

Biofilm Elimination and Caries Prevention using Multifunctional Nanocatalysts
The proposed approach using nanocatalysts that synergize with hydrogen peroxide may substantially advance current antibiofilm/anticaries modalities. It integrates a multifunctional strategy that is highly effective in degrading the EPS matrix and killing the bacteria embedded within biofilms, while preventing apatitic demineralization under acidic pH. Importantly, the agents are low cost and biocompatible, facilitating further clinical translation and product development to promote oral health.
Funding Source: NIH
Principal Investigator: Dr. Michel Koo, Professor

Department of Pathology
Role of a Novel Human Mast Cell G Protein Coupled Receptor in Allergy and Inflammation
Mast cells play important roles in allergic and inflammatory diseases. Dr. Ali’s lab has discovered a new receptor protein that is expressed on the surface of human mast cells. Understanding the molecular mechanism of its activation may provide new approaches to modulate allergic and inflammatory diseases.
Funding Source: NIH
Principal Investigator: Dr. Hydar Ali, Professor

Role of PERK Haplotypes in HIV-Associated Neurocognitive Disorders
The success of antiretroviral therapy in controlling HIV replication led to significant improvements in life expectancy. Consequently, the percentage of aging HIV-positive patients are increasing; however, age-related changes in the brain are becoming evident, impacting long-term behavioral and cognitive health of these individuals. This study will assess the mechanisms underlying HIV- and antiretroviral drug-mediated perturbations in cellular and molecular processes that are shown to be dysregulated in age-associated neurodegenerative processes, with the aim of identifying genetic risk factors that may contribute to these perturbations within the brains of HIV-positive patients.
Funding Source: NIH
Principal Investigator: Dr. Kelly Jordan Sciutto, Professor and Chair

Role of Heme Oxygenase-1 Microsatellite Polymorphisms in HIV-associated Neurocognitive Disorders: Utilizing Secoisolariciresinol Diglucose as a Targeted Therapeutic Approach in African American Patients
Human monocyte derived macrophages (hMDM) will be isolated from African American donors and non- African American donors and infected with various HIV tropism in the presence and absence of Secoisolariciresinol diglucose (SDG) to assess: infectivity, changes in secretory profiles, neurotoxicity, and HO-1 signaling.
Funding Source: Icahn School of Medicine at Mount Sinai
Principal Investigator: Dr. Kimberly Williams, Postdoctoral Fellow, Jordan-Sciutto Lab

Department of Pediatrics
Skeletal and Dental Quality in Adolescents with Urinary Stone Disease (USD)
The goals of this study are to: (1) compare high-resolution peripheral quantitative computed tomography (HR-pQCT) measures of trabecular and cortical microarchitecture and tibia and radius strength from micro-finite element analyses in 70 adolescents with USD and 70 healthy participants; (2) perform comprehensive assessment of dentition and its supporting tissues in adolescents with USD; and (3) determine modifiable mediators of bone and dental quality in USD by examining their associations with urinary metabolic profiling and dietary intake.
Funding Source: Children’s Hospital of Philadelphia
Principal Investigator: Dr. Evlambia Hajishengallis, Division Chief

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Penn
The Robert Schattner Center
University of Pennsylvania
School of Dental Medicine
240 South 40th Street
Philadelphia, PA 19104-6030