Luda Diatchenko - US grants

DESCRIPTION: (provided by the applicant) Painful temporomandibular disorder (TMD) is a very common orofacial pain condition that affects a large proportion of the human population with a strong bias towards females. The risk of developing TMD and the severity of the disease are associated with a generalized sensitivity to pain. In preliminary studies, we found that specific genetic variants (haplotypes) that code for catecholamine-O-methyltransferase (COMT), an enzyme regulating catecholamine levels, and Beta2-adrenergic receptor (Beta2-AR), a receptor target for epinephrine, are associated with human pain perception and the risk of developing a myogenous TMD. We propose to extend our preliminary assessments of selected SNPs by identifying and functionally characterizing the full haplotype structure of the genes that code for COMT and Beta2-AR. We will identify individual single nucleotide polymorphisms (SNPs) and haplotypes that are associated with pain perception, menstrual cycle related somatic complaints, and the risk of developing myogenous TMD. In order to accomplish this, we will conduct a case-control study on 200 female TMD patients and 200 female control patients. We will also conduct a series of biochemical and molecular biological studies that will examine the mechanisms by which polymorphisms in COMT and Beta2-AR genes affect the biological functions of the respective coded proteins. By elucidating the genetic factors that influence human pain perception, these studies will contribute to our understanding of the pathophysiology underlying myogenous TMD and may lead to new pharmacogenetic approaches to the diagnosis and treatment of TMD patients.

DESCRIPTION: (provided by the applicant) Painful temporomandibular disorder (TMD) is a very common orofacial pain condition that affects a large proportion of the human population with a strong bias towards females. The risk of developing TMD and the severity of the disease are associated with a generalized sensitivity to pain. In preliminary studies, we found that specific genetic variants (haplotypes) that code for catecholamine-O-methyltransferase (COMT), an enzyme regulating catecholamine levels, and Beta2-adrenergic receptor (Beta2-AR), a receptor target for epinephrine, are associated with human pain perception and the risk of developing a myogenous TMD. We propose to extend our preliminary assessments of selected SNPs by identifying and functionally characterizing the full haplotype structure of the genes that code for COMT and Beta2-AR. We will identify individual single nucleotide polymorphisms (SNPs) and haplotypes that are associated with pain perception, menstrual cycle related somatic complaints, and the risk of developing myogenous TMD. In order to accomplish this, we will conduct a case-control study on 200 female TMD patients and 200 female control patients. We will also conduct a series of biochemical and molecular biological studies that will examine the mechanisms by which polymorphisms in COMT and Beta2-AR genes affect the biological functions of the respective coded proteins. By elucidating the genetic factors that influence human pain perception, these studies will contribute to our understanding of the pathophysiology underlying myogenous TMD and may lead to new pharmacogenetic approaches to the diagnosis and treatment of TMD patients.

DESCRIPTION: (provided by the applicant) Painful temporomandibular disorder (TMD) is a very common orofacial pain condition that affects a large proportion of the human population with a strong bias towards females. The risk of developing TMD and the severity of the disease are associated with a generalized sensitivity to pain. In preliminary studies, we found that specific genetic variants (haplotypes) that code for catecholamine-O-methyltransferase (COMT), an enzyme regulating catecholamine levels, and Beta2-adrenergic receptor (Beta2-AR), a receptor target for epinephrine, are associated with human pain perception and the risk of developing a myogenous TMD. We propose to extend our preliminary assessments of selected SNPs by identifying and functionally characterizing the full haplotype structure of the genes that code for COMT and Beta2-AR. We will identify individual single nucleotide polymorphisms (SNPs) and haplotypes that are associated with pain perception, menstrual cycle related somatic complaints, and the risk of developing myogenous TMD. In order to accomplish this, we will conduct a case-control study on 200 female TMD patients and 200 female control patients. We will also conduct a series of biochemical and molecular biological studies that will examine the mechanisms by which polymorphisms in COMT and Beta2-AR genes affect the biological functions of the respective coded proteins. By elucidating the genetic factors that influence human pain perception, these studies will contribute to our understanding of the pathophysiology underlying myogenous TMD and may lead to new pharmacogenetic approaches to the diagnosis and treatment of TMD patients.

DESCRIPTION (provided by applicant): Temporomandibular Joint Disorders (TMJD) and Orofacial Pain (OFP) are complex and multi-factorial pain disorders involving genetic, social, cultural, biobehavioral, and environmental factors. To effectively manage these conditions, multi-and inter-disciplinary teams of TMJD and OFP basic and clinical researchers are needed to adequately address the multi-factorial nature of these conditions. This document represents an institutional response from the University of North Carolina at Chapel Hill (UNC-CH) School of Dentistry's (SOD) Center for Neurosensory Disorders (CNSD) to NIDCR PAR-11-289: Institutional Career Development Award for Enhancing Research Capacity in Temporomandibular Joint Disorders and Orofacial Pain (K12). The purpose of this proposed Biomedical Researcher Development Scholarship (BRDS) program is to develop a cohort of successful and independent basic, clinical and translational research scholars who can lead multi- disciplinary research teams to apply novel approaches to TMJD and OFP research that will improve the understanding of these disorders and lead to more effective methods of diagnosis and treatment. Our program embraces the full spectrum of basic, translational and clinical research including mechanisms of acute and chronic pain, therapeutic intervention, clinical trials, epidemiology, social, and behavioral clinical research related to TMJD, OFP and related comorbid pain disorders. A strong focus on the biopsychosocial and molecular genetic mechanisms that contribute to TMJD and OFP will be emphasized. BRD scholars will have the opportunity to carry out supervised biomedical, epidemiological, health services/health policy, or clinical research with the primary objective of developing or enhancing multi-disciplinary collaborative research skills and knowledge in preparation for an independent research career relevant to the mission of the NIDCR. This career development award proposes to enhance the research capacity of scholars in the field of TMJD and OFP research by achieving the following objectives: 1) To attract and engage junior or new basic and clinical investigators trained in sciences relevant to TMJD and OFP who are from diverse biomedical backgrounds into the field of TMJD and OFP research; 2) To mentor and nurture these research scholars and equip them with the necessary knowledge and skills to pursue independent research careers in TMJD and OFP; 3) To integrate the research scholars into a multi- and inter-disciplinary research environment that will foster the development of collaborative scientific advancement as well as enhance individual skills and expertise; 4) To assist BRD scholars with the development of K08, K23 or R series awards, or with other mechanisms of research training support and career development; 5) To groom these research scholars to become future leaders of multi- and inter-disciplinary collaborative research teams; and 6) To continue to support and mentor scholars following completion of their BRDS. Our goal is to create a new cadre of multi-disciplinary and highly interactive scientists who can serve as the next generation of TMJD and OFP research leaders. PUBLIC HEALTH RELEVANCE: The purpose of this proposed Biomedical Researcher Development Scholarship (BRDS) program is to develop successful and independent basic, clinical and translational research scholars who can lead multi-disciplinary research teams to apply novel approaches to TMJD and OFP research that will improve the understanding of these disorders and lead to more effective methods of diagnosis and treatment.

DESCRIPTION (provided by applicant): While virtually everyone experiences acute pain at some time, it is chronic pain that exacts a profound burden on the public health, reducing quality of life for tens of millions Americans, and incurring substantial health care costs. Yet little is known about mechanisms that cause a transition from acute to chronic pain; subsequently, event the best of treatments have limited efficacy. One likely clue regarding etiology is that patients who have one form of chronic pain often experience chronic pain elsewhere in the body. In this project, we hypothesize that the transition from acute to chronic pain and the development of multiple chronic pain conditions, are caused by specific constellations of genetic variants and phenotypic risk factors (ie. psychological distress, pain amplification and clinical pain characteristics). This hypothesis is based on our studies of temporomandibular disorder (TMD) in the multi-site OPPERA project (Orofacial Pain, Prospective Evaluation and Risk Assessment; NIH/NIDCR U01-DE017018). In 2006-08, we enrolled 3,263 healthy adults, 233 of whom developed acute TMD during the 3-year follow-up period. Risk factors for acute TMD differed conspicuously from genetic and phenotypic risk factors for chronic TMD. Furthermore, 86% of chronic TMD cases had one or more of four chronic, idiopathic pain conditions: headache (HA), low back pain (LBP), irritable bowel syndrome (IBS) or widespread bodily pain (WBP). In this competitive renewal application, we propose three new aims designed to reveal novel information regarding the etiology and pathophysiology of chronic pain. Aim 1: To identify phenotypes and genotypes that predict risk of transition from acute TMD to chronic TMD, we will enroll a new cohort of 1,000 adults who have acute TMD, following them for six months to identify an expected 400 who progress to chronic TMD. Aim 2 will identify risk factors for one or more of five: idiopathic pain conditions (IPCs): TMD, HA, LBP, IBS and/or WBP. Follow-up assessments will be conducted among people in the OPPERA-I prospective cohort study, identifying an expected 640 people who have ?1 IPC. Existing phenotypes and genotypes measured at baseline will be used to predict risk of 1 IPC vs. ?2 IPCs relative to controls. Aim 3 will identify genetic variants associated with chronic TMD. A discovery-phase genome wide association study (GWAS) will use existing DNA from 1,000 OPPERA-I chronic TMD cases and 1,000 OPPERA-I controls. Replication will use a new cohort of n=1,000 chronic TMD cases and n=1,000 controls. Those findings will be contrasted with GWAS analysis of the cohort for Aim 1 to identify genes that contribute differentially to acute and chronic TMD. Based on these findings and validated associations from other studies, twelve genes will be selected for exon sequencing of rare genetic variants. Knowledge generated from these proposed studies will have a significant impact on scientific understanding of risk factors for multiple, overlapping pai conditions. Moreover, the findings will be of direct benefit for clinicians and for their patients, elucidating mechanisms underlying chronic and idiopathic pain in people with TMD.