Panel 3: TMD Research Basic & Preclinical Future

Panel 3: TMD Research Basic & Preclinical Future Directions for Basic and Preclinical TMD Research TMD research over the years gaps, priorities, opportunities. Allen W. Cowley, Jr., PhD. Professor of Physiology Medical College of Wisconsin Chairman of TMJ Association Scientific Advisory Committee Over the years - Eight Scientific Meetings of The TMJ Association Sponsored by TMJ Association, NIDCR and other NIH Institutes and Offices. Meetings driven based upon an awareness that there was no coherent body of knowledge on the etiology and pathogenesis of TMD. Goals were to analyze the state of current research and bring new ideas and perspectives to the field. Resulted in recommendations to NIH regarding gaps and opportunities in TMD basic and clinical sciences.

Patients and young investigators were an integral part of these meetings. www.tmj.org What did we learn? The pathophysiological basis of TMD remains an enigma. Found many hypotheses related to etiology but none validated. Found a lack of clinical definition: What is TMD? One or many diseases? Importantly, TMD was recognized as more than a problem of jaw dysfunction and pain in the jaw joint. TMDs do not exist alone - collection of disorders/comorbidities currently scientifically and clinically siloed. Chronic pain temporomandibular joint and muscle disorders (TMJDs) do not exist alone. They are part of a collection of

disorders that are both influenced by, as well as influence, other medical conditions such as chronic fatigue syndrome, cardiovascular disorders, hearing problems such as tinnitus, digestive and gastrointestinal disorders, and sleep disorders, to name a few. In short, TMDs are part of a very complex system. Lawrence A. Tabak, D.D.S., Ph.D. Director, National Institute of Dental and Craniofacial Research TMJ Science Vol 4, 2007 Generalized muscle pain Arthritis Allergy/ Immunity

Connective tissue disorders TMD Fatigue Sleep disorders Dysautonomias Depression IBS Center concept proposed multidisciplinary, integrated patient care and research. Patient Database Training Programs Scientific Cores

Chronic pain NIH Research Grants (RO1s; PPGs; Ks) CTSA Arthritis Allergy/ Immunity Connective tissue disorders Health Care Providers - biostatistics - genetics - proteomics, - bioinformatics

Generalized muscle pain TMD Fatigue Sleep disorders Dysautonomias Depression IBS Academic Health Centers Medical, Pharmacy, Dental Schools.

Affiliated Community Hospitals, and Dental Clinics The TMJ Patient-Led RoundTable (2016 ongoing) A public private partnership bringing together all A public private partnership bringing together alloral stakeholders patients, scientists, bioengineers, stakeholders patients, scientists, bioengineers, oral surgeons, device

manufacturers, NIH, FDA, AHRQ, surgeons, device manufacturers, NIH, FDA, AHRQ, insurance industry, patient reported outcome experts insurance patientinreported outcome experts and othersindustry, - with interest TMDs and with the and others - with

interest inthe TMDs and withofthe common goal of improving healthcare patients. common goal of improving the healthcare of patients. Working Group 1: TMJ Patient-Led RoundTable Gaps/Opportunities Identified in Basic Science related to TMD Molecular genomics and epigenetics. TMD and Data Science/Informatics Mechanisms underlying chronic TMD pain and joint specific pain. Sex difference Neuro-endocrine system interactions Immune/Inflammatory mechanisms (CNS/systemic) TM joint tissues and mechanics TM joint tissue engineering and disk replacements.

Animal models Working Group 1: TMJ Patient-Led RoundTable Gaps/Opportunities Identified in Basic Science related to TMD Molecular genomics and epigenetics. o Integrated investigation of genetic polymorphisms, gene expression, epigenetic markers, nucleosome localization and genome interactions for cell populations and at the single-cell level in TMD relevant tissue types versus normal. o NGS for genomic/epigenomic/proteomic/biomic/immune profiling. o Associations of novel genetic loci and non-coding mutations with welldefined phenotypes of TMD subjects. TMD and Data Science/Biomedical Informatics o Data science/biomedical informatics for advanced data analysis; artificial intelligence, machine learning, novel clustering methods for precise ID of disease risk, therapeutic effectiveness and outcomes of TMD subjects. o Bioinformatic approaches that vertically integrate pathway analysis. Working Group 1: TMJ Patient-Led RoundTable

Gaps/Opportunities Identified in Basic Science related to TMD Mechanisms underlying chronic TMD pain and joint specific pain (animal models and humans). o Quantitative sensory testing; mechanisms of peripheral and central sensitization. Sex differences o Effects of sex hormones upon disease initiation, progression and responses to drug treatments, surgical interventions and implants. Neuro-endocrine system interactions o Stress induced pathophysiological mechanisms and epigenetic responses related to TMD progression (PTSD, social isolation, etc.). Working Group 1: TMJ Patient-Led RoundTable Gaps/Opportunities Identified in Basic Science related to TMD Immune/Inflammatory mechanisms o Role of innate and adaptive immunity; inflammation & cytokines in onset and progression of TMD; responses to surgical procedures

and implant devices. TM joint tissues and mechanics o Developmental biology of the joint and related tissues. o Unique characteristics of jaw joint and other tissues (ligaments/muscles/blood vessels/nerves/collagens/extracellular matrixes). o Joint mechanics . Tissue engineering of TM joint and disk replacements. o Cellular models of TM joint tissues and TM muscles. o Novel materials o Regenerative medicine approaches Working Group 1: TMJ Patient-Led RoundTable Gaps/Opportunities Identified in Basic Science related to TMD Animal Models. o Model organisms that mimic important aspects of the complex human condition. o Genetically engineered models (rat/mouse; CRISPR-Cas9) based on GWAS associations in humans to study mechanisms.

TMD must be studied as a complex disorder determined by interacting and redundant systems. Understanding the etiology of TMD from only one perspective has failed (e.g. candidate genes, TM joint, muscle, hormones, brain, pain, immune/inflammation, etc. each alone are insufficient). Needed - information obtained with genome/omics sciences together with system-wide phenotyping to provide molecular/cellular/organ determinants of TM function and disease. Big gap: basic-translational research = integrated functional genomics. TMD phenotypes TMD phenotypes

Big gap: basic-translational research = integrated functional genomics. TMD phenotypes TMD phenotypes Big gap: basic-translational research = integrated functional genomics. Gene editing CRISPR/Cas9 ES/IPS cells Organoids TMD phenotypes TMD phenotypes Integration and convergence of complex multiscale systems needed to achieve an understanding of the interacting molecular/cellular/organ

determinants of TM functions and TMD. Convergence ? Emergent properties Physiology Medicine A matrix of dynamic molecular and physiological systems connected to genetic maps Facts NIDCR funding of TMD Research versus overall funding. $ 500000000 450000000 400000000

350000000 300000000 250000000 200000000 TMJ research (2017) = 3-4% of total NIDCR ($11.2 million vs total $371 million). 150000000 100000000 50000000 0 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 TMD affects approximately 36 million people in the U.S. NIDCR Extramural Funding to All Organizations (2017) Other $ 2.3 million 20.34%

3.82% 4.06% Medical Schools $2.6 million 47.83% Dental Schools $5.3 million 23.70% 0.26% Dental Schools Other Organizations Dental Organizations Medical Schools

Hospitals Small Businesses NIDCR funded 36 TMD related research grants in FY 18 Project Title Project titles Pain neural basis:..n=11 Pain sex differences:.n=2 Emotion dysregulation/sleep/bruxism:...n=3 Structure-function (ligaments/collagen/ECM elements/cartilage/chondrocyte/bone):..n=4 TMJ disc regeneration/bioscaffolds/stem cells:n=7 Genetics:.n=2 Immune factors:.n=1 Risk factors:n=1 Therapy/drug delivery:..n=2 Training K-99:n=1

Other NIH Institutes funding of TMD (n=5) The neural basis of touch and proprioception in the primate orofacial sensorimotor cortex TMJ Disc Regeneration Development of Drug Delivery Technology for Stem Cell-Based TMJ Regeneration Modeling temporomandibular joint disorders pain: role of transient receptor potential ion channels Genetic and post-translational modifications of TRPV1 in craniofacial pain Chronic orofacial pain: genetics, cognitive-emotional factors, and endogenous modulatory systems Structure-function relationships between human temporomandibular lateral capsule-ligament complex tensile stiffness, collagen ultrastructure an d ECM composition: Investigation of sexual dimorphisms Progenitor Regulation in Craniofacial Development and Regeneration Investigation and Modulation of the Mu-Opioid Mechanism in Chronic TMD (in vivo) Investigation and Modulation of the Mu-Opioid Mechanism in Chronic TMD (in vivo) Investigation of Risk Factors for Development of TMJD Pathology NIDCR Dentist Scientist K99:Improve TMJ Fibrocartilage Regeneration Strategies Chondrocyte-derived bone cells determine the overall pattern of TMJ condyle and contribute to bone remodeling Emotion Dysregulation and Sleep-Time Masticatory Muscle Activity in Sleep Bruxism Emotion Dysregulation and Sleep-Time Masticatory Muscle Activity in Sleep Bruxism Emotion Dysregulation and Sleep-Time Masticatory Muscle Activity in Sleep Bruxism Mechanism of Nociception Induced by Innocuous Cold in Trigeminal System Mechanistic Characterization of Pain in Temporomandibular Disorders: Does Pain Centralization Influence Responsiveness to Peripherally Targeted

Treatments? Role of Descending Pain Modulation System in Orofacial Pain Mechanisms of TMJ development and long-term function Molecular Roles of Cdk5 in Neuronal Functions and Pain Signaling TMJ Disc Regeneration by 3D-Printed Bioscaffolds in a Pre-Clinical Animal Model Cellular and Mechanical Mechanisms Regulating Mandibular Distraction Osteogenesis Brain Connectivity Patterns in Chronic Temporomandibular Joint Disorders Chondrocyte-pericellular matrix derived signaling maintains tissue integrity in the temporomandibular joint Immune activation of the endogenous control of persistent pain Central mechanisms underlying sex differences in endogenous pain modulation The Requirement of ADAMTS5-mediated Cleavage of Aggrecan in Temporomandibular Joint Development Neuroplasticity and the role of sensorimotor cortex in control of orofacial funct Mechanisms of Secondary Cartilage Induction and Maintenance in the Jaw Endogenous stem cells in jaw joint cartilage and ligament regeneration Effect of COMT genetic polymorphisms on response to propranolol therapy in Temporomandibular Disorder The Temporomandibular Disc: Biology and Regeneration Mechanism of BMP2 regulation of Mandibular Condylar Cartilage Growth TMD research greatly lagging in molecular genomic fields. Number of publications listed in PubMed (March 2019) indicating omic research in TMD/TMJ research compared to cardiovascular, kidney and pain.

Cardiovascular Kidney genomics 8232 proteomics 3500 metabolomics 1425 epigenome 247 biome 1015 4387 2288 917 97 760 14,419

8449 TMD/TMJ 65 32 2 0 9 Pain 1050 444 241 20 276 108 2013 Disconnect between Dental and Medical School

Basic and Translational Research * 1. Generally there remains paltry basic research collaborations with Dental and Medical School researchers. 2. NIDCR funding for TMD related basic research is very limited even in the top 5 research ranked Dental Schools. 3. Aggressive efforts to stimulate an integrated approach to study TMD are lacking. The science and funding siloes represent a great impediment to progress in this field. 4. Little evidence of efforts to comprehensively integrate cell/tissue specific functions with those of the whole organism. * Based on NIH grant titles and self-reported data from University web-sites. Blue Ridge Institute for Medical Research (BRIMR.ORG) 3X more Medical Schools with 70 X more funded research. US Medical Schools (n=147): US Dental Schools (n=51): $14,328,627,745 (updated Feb 2019) $202,866,311 (updated Feb 2019) Far fewer Dental School faculty with NIH funded

research. TMD is not a priority of Dental School research. NIH wide funding for TMD related basic research is difficult to obtain since reporting is not broken down in this manner. Summary of Gaps & Needs for TMD Basic Science It is necessary to extend TMD basic and translational research beyond the narrow province of dentistry to include the basic scientific and clinical disciplines needed to study this complex disorder. Basic research in Dental Schools would greatly benefit from collaborations with Medical School faculty, Schools of Bioengineering, Pharmacy School, and related shared core facilities.

Advances in the basic sciences related to TMD need to be coordinated via a trans-Institute/Agency research planning group to set goals based on exciting scientific and clinical missions that will attract basic, clinical, translational scientists and engineers to the field. Summary of Gaps & Needs for TMD Basic Science Patients expertise should be sought to identify and help focus broad research areas of greatest relevance to them. Every aspect of basic and clinical TMD research needs a significant increase of funding to attract scientists from those disciplines essential to develop teams of experts to address the obvious gaps in this field. Biggest gap: Lack of integration of knowledge from cell to organism.

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