This Project Grant award of $169,560.00, provided by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) under the Arthritis, Musculoskeletal and Skin Diseases Research program (CFDA 93.846), supports research to characterize the cutaneous opioid circuitry and its role in regulating skin inflammation and sensory perception. The primary goals are to: 1) identify the cellular sources of the endogenous opioid enkephalin and its functions in homeostasis and...
This federal Project Grant award from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), under the Arthritis, Musculoskeletal and Skin Diseases Research program (CFDA 93.846), provides $343,904 to The Regents of the University of California, San Francisco to investigate transcriptional abnormalities in skin-resident T cells as potential biomarkers for atopic dermatitis in Asian and Hispanic genetic backgrounds. The research aims to validate an abnormal atopic T...
This Project Grant award from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), under the Arthritis, Musculoskeletal and Skin Diseases Research program (CFDA 93.846), will provide $401,433 from September 2023 to August 2025 to support research at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. The research aims to investigate the role of protein O-GlcNAcylation in regulating keratinocyte function and its impact on skin...
The federal Project Grant award number K08AR085193 was provided by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) under the Arthritis, Musculoskeletal and Skin Diseases Research program (CFDA 93.846). The $176,148 award will fund a 5-year research and career development plan led by Dr. Maxime Kinet at the University of California, San Francisco (UCSF) to study the role of PI16-expressing fibroblasts in mouse and human fibrosing skin diseases. The research...
The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) awarded a $172,700 Project Grant (CFDA 93.846 - Arthritis, Musculoskeletal and Skin Diseases Research) to the University of California, Irvine. This grant will fund the development and characterization of recombinant, cell-penetrating botulinum protease variants that can inhibit the release of neuropeptides and cytokines in neurons and immune cells, respectively. The goal is to create a new topical therapeutic...
The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) awarded a $628,968 project grant (CFDA 93.846 - Arthritis, Musculoskeletal and Skin Diseases Research) to The Regents of the University of California, San Francisco (UCSF) to define and treat genetic abnormalities in psoriasis/atopic dermatitis-overlap dermatoses. The project aims to use high-resolution, quantitative biomarkers to understand the etiology of these "PSO-AD" rashes and determine if they...
This Project Grant award from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), under the Arthritis, Musculoskeletal and Skin Diseases Research program (CFDA 93.846), will support research to define the role and regulation of the differentiation-specific keratin KRT9/K9 in the adaptation of keratinocytes to mechanical stress in the palmoplantar (glabrous) skin. The $208,160.00 award to the Regents of the University of Michigan will fund a study hypothesizing that...
This Project Grant award of $167,230 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), under the Arthritis, Musculoskeletal and Skin Diseases Research program (CFDA 93.846), supports research to discover the genetic and molecular mechanisms underlying comedogenesis, the formation of comedones or plugs that occlude hair follicles. The research, to be conducted by Yale University, leverages studies of rare mosaic genodermatoses, or genetic skin disorders, to...
This $126,174 federal Project Grant awarded on May 29, 2025 by the National Institute of Allergy and Infectious Diseases (CFDA 93.855 Allergy and Infectious Diseases Research program) will support research at the University of California, Davis to investigate the local immune response in bacterial skin infections using a novel skin-on-a-chip model. The overarching goals are to gain mechanistic insights into the migration of hematopoietic stem and progenitor cells (HSPCs) into human skin and...
This Project Grant award from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), under the Arthritis, Musculoskeletal and Skin Diseases Research program (CFDA 93.846), aims to create and validate transgenic mouse models that genetically and phenotypically recapitulate Pachyonychia Congenita (PC), a rare skin disease. The $556,034 award, effective August 1, 2024 through June 30, 2026, will support the University of Michigan in completing the characterization of a...
KERATINOCYTE-DEPENDENT REGULATION OF INNATE IMMUNE RESPONSES IN INFLAMED SKIN - SUMMARY INFLAMMATION, DYSREGULATED INNATE IMMUNE RESPONSES, AND LOSS OF BARRIER FUNCTION UNDERLIE SEVERAL SKIN CONDITIONS INCLUDING PSORIASIS, ATOPIC DERMATITIS, HIDRADENITIS SUPPURATIVA, AND PACHYONYCHIA CONGENITA. COMPELLING EVIDENCE NOW SHOWS THAT SIGNALS REGULATING INFLAMMATION AND INNATE IMMUNITY ARE PRODUCED AND SECRETED BY STRESSED KERATINOCYTES MAKING UP THE SKIN EPIDERMIS. HOW THE RELEVANT SIGNALS ARE GENERATED IN KERATINOCYTES, THEIR CELLULAR TARGETS, AND THE PATHWAYS INVOLVED IN ENSURING PROPER REGULATION OF INFLAMMATION AND INNATE IMMUNITY IN HEALTHY SKIN TISSUE, AND THEIR DYSREGULATION IN DISEASE, REMAIN POORLY UNDERSTOOD. THIS MULTI-PI PROPOSAL TAKES ADVANTAGE OF THE COMPLEMENTARY EXPERTISE OF TWO ESTABLISHED INVESTIGATORS AND IS SUPPORTED BY A STRONG BODY OF UNPUBLISHED FINDINGS, OBTAINED COLLABORATIVELY, SHOWING THAT (I) KERATINOCYTE- DERIVED AND KERATIN-DEPENDENT SIGNALS REGULATE THE SPATIAL AND TEMPORAL PATTERN OF NEUTROPHIL INFLUX INTO SKIN UNDERGOING STERILE INFLAMMATION; (II) KERATINOCYTES TRANSIENTLY ADAPT TO PRIOR EXPOSURES AND ARE ABLE TO AMPLIFY RESPONSES IN THE SETTING OF REPEATED AGGRESSIONS; (III) THE STRESS RESPONSE KERATIN 17 (K17) ACTS AS A POSITIVE REGULATOR OF NEUTROPHIL INFILTRATION BY MEDIATING THE SUSTAINED ACTIVITY OF PROTEIN KINASE C A (PKCA) IN ACTIVATED KERATINOCYTES; AND (IV) KERATIN 16 (K16) - ANOTHER STRESS RESPONSE KERATIN - ACTS AS A NEGATIVE REGULATOR OF NEUTROPHIL INFILTRATION AND INFLAMMATION. WE HYPOTHESIZE THAT STRESSED KERATINOCYTE-DERIVED SIGNALS ENGAGE AND REGULATE CELLULAR EFFECTOR OF INNATE IMMUNITY IN SKIN, AND THAT THIS IS HIGHLY RELEVANT TO SEVERAL INFLAMMATORY SKIN DISORDERS. WE FURTHER HYPOTHESIZE THAT K16 AND K17 ACT THROUGH UNIQUE CIS-ACTING DETERMINANTS TO DIFFERENTIALLY REGULATE PKCA ACTIVITY, NEUTROPHIL INFILTRATION AND OTHER ASPECTS OF INNATE IMMUNITY IN STRESSED SKIN TISSUE. THE PROPOSAL TESTS THESE HYPOTHESES THROUGH THREE SPECIFIC AIMS. AIM 1 SEEKS TO COMPARE THE SPATIOTEMPORAL PATTERN OF IMMUNE CELL INFILTRATION AND PKCA ACTIVITY IN MOUSE SKIN NULL FOR EITHER KERATIN 16 OR 17 FOLLOWING EXPOSURE TO STRESSORS. THESE ANIMALS STUDIES WILL BE CORROBORATED BY STUDIES IN N-TERT HUMAN KERATINOCYTES IN CULTURE. AIM 2 SEEKS TO IDENTIFY, IN CELL CULTURE MODELS, THE CIS- ACTING DETERMINANTS RESPONSIBLE FOR THE DIFFERENTIAL IMPACT OF K16 AND K17 PROTEIN ON PKCA ACTIVITY, NEUTROPHIL STIMULATION AND OTHER CELLULAR ASPECTS OF INFLAMMATION AND INNATE IMMUNITY. FINALLY, AIM 3 WILL DEFINE THE CONTRIBUTION OF OTHER KEY CELLULAR EFFECTORS OF INNATE IMMUNITY, SPECIFICALLY MACROPHAGES, IN MEDIATING THE KERATINOCYTE- AND KERATIN-DEPENDENT AMPLIFICATION OF NEUTROPHIL INFLUX IN STRESSED SKIN IN VIVO. THE MECHANISTIC INSIGHT THAT WE STAND TO GAIN FROM COMPLETING THIS PROJECT IS PREDICTED TO LEAD TO A DEEPER UNDERSTANDING OF THE PATHOPHYSIOLOGY OF CHRONIC SKIN INFLAMMATORY DISORDERS, YIELD NOVEL AND MORE RELIABLE BIOMARKERS AND, POSSIBLY, NEW STRATEGIES TO TREAT SKIN DISEASES.