The following description was taken from the R01 version of this FOA.
This Funding Opportunity Announcement (FOA) will support basic and translational studies aimed at understanding the etiology, and the cellular and molecular mechanisms, including the environmental, genetic, epigenetic, biologic, and immunologic factors causing and/or associated with Hidradenitis Suppurativa (HS), a complex, chronic, inflammatory skin disease characterized by recurrent, painful, erythematous nodules and suppuration in different areas of the body, such as the axilla, genitofemoral area, perineum, and gluteal areas. Nodules, sinus tracts and abscesses can develop fast, and it is unpredictable when and where they might burst. As a result, HS is associated with a significant negative impact in patients’ quality of life. There are no biological or pathological tests to diagnose HS, which is defined only by its clinical features.
Disease etiology and pathobiology are poorly understood, and available treatments are limited and/or suboptimal. Even though it is well known that HS is the result of follicular hyperkeratosis and hyperplasia at the infundibulum which results in follicular occlusion, little is known about the mechanisms by which the structure and function of the pilosebaceous-apocrine unit is deregulated. In addition, it is unclear whether and/or how the absence of sweat gland proteins, the gamma secretase mutations, and the apocrine gland variation are contributing to HS pathogenesis. Follicular occlusion with continual apocrine gland secretion results in perifollicular cyst formation and trapping of commensal bacteria. A key feature of advanced HS is the existence of dermal tunnels coated with bacterial biofilms. The biological mechanisms leading to the progression of HS from erythematous nodules to the formation of persistent, suppurative, epithelized tunnels are not well understood. The persistence of these structures may explain why HS is difficult to treat. Rupture of the cysts into the dermis results in the activation of cutaneous and systemic innate and adaptive immunity, and suppuration of bacterial commensals. Cutaneous innate immunity is activated by different mechanisms, including TLR2 and inflammasome activation, and follicular keratinocyte responses. Chronic inflammatory cells have been identified in lesional skin, as well as anti-microbial peptides, metalloproteinases, and pro-inflammatory cytokines and chemokines, which are overexpressed in the HS suppurative discharge in addition to lesional skin. However, the relative contribution of cutaneous and systemic innate and adaptive immune responses to the pathobiology of HS is not well understood. In addition, cutaneous transcriptomic signatures of lesional HS biopsies revealed differentially expressed pathways, such as granulocyte and agranulocyte adhesion and diapedesis, atherosclerosis signaling, interferon signaling and others. Yet, the mechanisms by which these signatures contribute to HS pathobiology has not been established. On the other hand, the TNF-a, IL-1 and IL-23 cytokines are differently expressed in HS, yet it is unclear to what extent these cytokines are associated with HS pathobiology beyond promoting inflammation.
Furthermore, HS may be considered as a model of chronic wound, in which the biofilms produced by the bacterial commensals in the dermal tunnels protect them from immune attack and further stimulate local inflammation. Yet, the cellular and molecular mechanisms that promote chronic wound and/or prevent wound-healing are ill understood. Importantly, 30%–40% of patients reported a family history of HS, but the genetic architecture of HS is poorly defined. Genetic mutations in genes that encode gamma secretase proteins have been discovered in up to 5% of HS patients, however it is unclear how these mutated genes are functionally associated with disease pathobiology. In addition, genome wide association studies and epigenetic studies have never been conducted, in patients with HS.
Risk factors contributing to HS pathobiology include the deregulation of hormonal metabolism and obesity, the skin microbiome, cigarette smoke and stress. Nevertheless, the mechanisms by which each of these risk factors contribute to and/or exacerbate HS pathobiology are ill defined. In addition, there are comorbidities associated with HS, including psychological conditions (anxiety and depression), metabolic syndrome, hypertension, hypertriglyceridemia, low-HDL, and diabetes. The mechanism by which these comorbidities impact HS pathobiology are not well defined. Finally, there are rheumatic diseases (spondyloarthropathy and inflammatory arthritis), gastroenterological diseases (inflammatory bowel disease and pilonidal sinus) and endocrinological (polycystic ovarian syndrome) diseases that are associated with HS, and it unclear if and/or how these conditions contribute to HS pathobiology.
Areas of Interest
NIAMS intends to encourage projects from relevant research communities that improve our knowledge of HS in the broadest biological sense, and accelerate the application of recent findings in disease model systems to advance our understanding of HS etiology and pathobiology. Areas of interest include, but are not limited to the following:
- Mechanisms based diagnosis,
- Deregulation of the structure and function of the pilosebaceous-apocrine unit,
- Role of gamma secretase mutations, and apocrine gland variation on disease pathobiology,
- Determining the progression of HS from nodules to the formation of suppurative tunnels,
- Identification of HS triggers and flares,
- Role of cutaneous and systemic innate and adaptive immune responses in HS pathobiology,
- Signaling pathways causing and/or associated with disease pathobiology,
- Identifying unique omics signatures and biomarkers associated with disease pathobiology,
- HS as a disease model of chronic wounds and mechanism preventing wound healing,
- Genetic and epigenetic susceptibility studies,
- Mechanisms of comorbidities, risks factors, and associated diseases contributing to HS pathobiology,
- Identification of new potential drug targets.
Deadlines: standard dates apply
- R01 – https://grants.nih.gov/grants/guide/pa-files/PA-18-719.html
- R21 – https://grants.nih.gov/grants/guide/pa-files/PA-18-718.html
Filed Under: Funding Opportunities