National Advisory Dental and Craniofacial Research Council
The goal of this initiative is to encourage research on mechanisms underlying male/female-based differences in Dental, Oral, and Craniofacial (DOC)-related diseases and conditions. Specifically, this initiative encourages studies aimed at understanding immune reactivity, genetic and environmental triggers, and hormonal changes as they relate to male/female-based differences in DOC-related diseases and conditions including, but not limited to, Sjögren’s Syndrome (SS), orofacial pain, temporomandibular joint (TMJ) disorder (TMD), and HPV-associated oropharyngeal cancers and salivary gland tumors.
It is now recognized that chronic diseases affect women and men differently, and DOC diseases and conditions, such as SS, orofacial pain, TMD, salivary gland tumors, and oropharyngeal cancers are no exception. Substantial differences, both in presentation and in challenges to long-term management, exist between males and females with these conditions. However, critical scientific gaps remain in our understanding of the underlying mechanisms of male/female-based differences in disease onset, progression, and persistence, as well as consequences for daily functioning, and responses to treatment.
Many autoimmune diseases, including SS, exhibit a greater incidence rate (IR) in females; in fact, SS is one with the highest female preponderance among all autoimmune diseases of about 9:1. SS is characterized by lymphocytic infiltration of salivary and lacrimal glands resulting in irreversible tissue damage, causing dry mouth and dry eyes as well as other systemic manifestations, including an increased risk for non-Hodgkin B-cell lymphoma. SS primarily affects post-menopausal women, suggesting a role for sex hormones in disease development. While previous studies have focused on clinical differences between men and women with SS, to date, the mechanism of this difference is not understood (Díaz-López etal. 2004). In addition, limited data exist on the severity of disease in men verses women. Thus far, genome wide association studies (GWAS) have focused on the presence or absence of SS as made by clinical diagnosis (Lessard et al. 2013 and Li et al.2013). Interestingly, studies have revealed that men with Klinefelter syndrome (XXY males) develop autoimmune diseases, specifically systemic lupus erythematosus (SLE), at rates similar to females (Scofield et al. 2008 and Dillon et al. 2010). Recent studies on X-chromosome inactivation report that at least 10% of the X-chromosome escapes inactivation potentially leading to over-expression of certain gene products in females (Broen et al. 2010). Many of the genes on the X-chromosome are involved in the immune response. In addition to genetics, sex hormones, environmental factors, and infections have also been reported to play a role in autoimmune disease, including SS.
TMD, a heterogeneous disorder often characterized by pain and dysfunction in the TMJ and muscles that control jaw movement, primarily affects women of childbearing age and falls off sharply with advancing middle age. Females demonstrate 4-fold greater odds of TMD relative to males (Fillingim et al. 2011) and a greater risk of transition from acute to chronic pain status. Earlier studies showed that TMD pain intensity is linked to hormonal fluctuations and that estradiol can modulate facial pain (Turner et al. 2011 and Smith et al. 2006). Further, data suggest that female hormones may play an important role in the development and persistence of this condition. Recent evidence from the NIDCR-supported Orofacial Pain Prospective Evaluation and Risk Assessment (OPPERA) study indicates that while females have significantly greater odds of developing chronic TMD, the IR of first-onset TMD in females is only marginally greater than in males (Slade et al.2013). Pain hypersensitivity in male and female mice is differentially dependent on microglia and T cells, and implies a sex-specific response to microglia targeted pain treatments (Sorge et al. 2015). The etiology and mechanisms of another orofacial pain condition, burning mouth syndrome (BMS) that disproportionately affects postmenopausal women remain largely unknown. Collectively, women are greatly overrepresented among patients with other chronic pain conditions that can overlap with orofacial pain, including migraine, fibromyalgia, chronic fatigue syndrome, and interstitial cystitis. A firm understanding of whether different overlapping pain conditions share mechanisms involving general central nervous system dysfunction, the nature of the mechanisms behind orofacial pain conditions affecting females vs. males as well as a detailed characterization of female vs. male disorder-specific symptoms, is lacking.
Cancers of the oral cavity and salivary glands show disproportionate IR in men and women and the basis of these differences are not well understood. Males have a 51% higher combined IR of the major salivary gland carcinomas, but the IR varies significantly within the subtypes of salivary gland carcinomas. For example, females show 25 -38% higher (age-adjusted below 50 years of age) IR of adenoid cystic, acinic cell and muco-epidermoid carcinoma whereas men show 122% higher IR of squamous cell carcinomas of the salivary gland (Boukheris et al. 2009). Interestingly, HPV-associated oropharyngeal cancers are 3-5 fold more common in men than women, which correlates only partially (~18%) with behavioral risk factors (Chaturvedi et al. 2015). Recent studies indicate that males have lower seroconversion rates upon HPV infection compared to females (Giuliano et al. 2015).
These and other critical advances identified a strong need to elucidate underlying mechanisms of male/female-based differences in DOC-related diseases and conditions.
Gaps and Opportunities
A wealth of available information about male/female differences in IR for a number of DOC diseases points to the importance of considering sex when examining the underlying mechanisms of disease. It is well-established that women demonstrate increased immune reactivity, increased levels of IgM, and a stronger humoral and cellular immune responses to antigens, compared to men. Advancing our understanding of the underlying mechanisms leading to this skewed representation is likely to result in the identification of new therapeutic targets and lead to the development of precision medicine-based therapies and behavioral interventions.
Research topics of interest include but are not limited to:
- Identification of human genetic risk factors and protective factors, gene polymorphisms, and gene-environment interactions that contribute to sex-related differences in DOC diseases
- Identification of molecular pathways and cellular networks controlling sex-based differences, and elucidation of how these pathways and networks influence disease onset, progression, and persistence, as well as responses to treatment
- Elucidation of sex hormone influence on differences in plastic responses in DOC-related diseases
- Identification of sex-based differences in pain coping strategies SS-specific topics:
- Identification of the critical triggers and environmental factors, such as infection with Epstein-Barr virus, related to sex-based differences in SS
- Characterization of sex-based regulation of autoimmune mechanisms and immune reactivity that initiate and control inflammatory responses and immune activation in SS
- Enhanced understanding of the potential differences in severity of SS in men verses women and unravelling mechanisms behind such differences
- Identification of the mechanisms of differential immune responses against HPV infection between males and females to inform better sex-specific strategies for disease prevention and control
- Comparative analysis and mechanistic studies of seroconversion rates among men and women
- Further analysis of the molecular basis of sex-specific differences in IRs within specific subtypes of salivary gland tumors
- Elucidation of sex influences associated with TMD and orofacial pain in disease onset, experience of TMD pain, response to biobehavioral treatments, and transition from acute to chronic pain status
- Assessment of sex-related differences in target sites, mechanisms, and effects of neuromodulators on neuronal events associated with TMD and orofacial pain conditions
- Identification of sex-based differences in mechanisms of neuroimmune pain transmission in TMD and orofacial pain conditions
- Clarification of unconscious sex/gender-based biases responsible for inequities in pain management treatment planning
Current Portfolio Overview
Projects addressing the understanding of mechanisms underlying male/female-based differences in DOC-related diseases and conditions are underrepresented in the NIDCR extramural research portfolio. A search of recent NIDCR research project grants (2013–2015) associated with SS, orofacial pain, TMD, HPV-associated oropharyngeal cancers, and salivary gland tumors identified 109 projects in these areas. Of these projects 28% were focused on SS, 39% on pain and 32% on cancer. A more focused search, specifically targeting sex-based differences in these diseases demonstrates the need to consider this concept proposal: only 3% of these NIDCR funded grants are actively investigating sex-based differences. Although other NIH Institutes also fund research in these general research areas, there are a limited number of grants currently examining sex-based differences in DOC-related diseases and conditions across NIH.
NIDCR’s investment in both the Sjögren’s International Collaborative Clinical Alliance (SICCA) Biorepository ( >3000 female samples and >300 male samples are available) and the Salivary Gland Tumor Biorepository (SGTB) provide well-characterized biological materials from patients to help investigators design studies to better understand mechanisms of differential DOC diseases and conditions.
Alignment with Institute Goals and Strategic Plan
This concept aligns with the goals and objectives of NIDCR Strategic Plan 2014–2019: Goal I, Objective 1-1: Enable basic research to advance knowledge of dental, oral, and craniofacial health; Goal 2, Objective 2-1: Support research toward precise classification, prevention, and treatment of dental, oral, and craniofacial health and disease.
Overlapping Interests with Other NIH Institutes and Centers
Explorations, as addressed by this initiative, will stimulate interest and potential for partnerships with other NIH Institutes and Centers such as ORWH, NEI, NIAID, NIAMS, NINDS, and NCI, which share common interests with NIDCR in several diseases.
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