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Principal Investigator: Bahram Razani
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $189,000
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
PROJECT SUMMARY: The relationship between psoriatic skin and joint disease remains enigmatic. A subset
of patients with psoriasis develop arthritis, early diagnosis of which is challenging. Additionally, therapies for
skin disease are less successful at treating arthritis. A20 (Tnfaip3) is a broadly-expressed protein that restricts
multiple inflammatory signaling pathways and is genetically associated with both psoriasis and psoriatic
arthritis in humans. However, the molecular and tissue-specific mechanisms by which A20 restricts psoriatic
disease are unknown. Our preliminary data shows that A20's capacity for binding linear ubiquitin is critical for
preventing distal digit psoriatic skin and joint disease in mice, with pathology requiring TNF, IL17A, and T-cells.
Early disease surrounded the epidermis; therefore, we generated mice allowing inducible deletion of A20 only
in keratinocytes in adulthood (A20iEKO mice). Remarkably, these mice also develop similar psoriatic skin and
joint disease that requires TNF, IL17A, and T-cells. I aim to determine the immune mechanisms by which A20
dysregulation in keratinocytes orchestrates skin and joint disease. Aim 1 centers around understanding the
cytokine requirements for coordinating the pathogenic immune infiltrate. In Aim 2 I will dissect the role of T-
cells by determining which subsets or antigen-specific cells are critical for pathogenic cytokine secretion as
well as their anatomical sites of action. Aim 3 focuses on the cell-intrinsic role of A20 in keratinocytes, where I
plan to understand the mechanisms by which A20 restricts inflammatory pathways in vivo, during keratinocyte
differentiation, and downstream TNFR and IL17R. Together, these studies will reveal how keratinocytes can
orchestrate an inflammatory process that results in psoriatic skin and joint disease. This is relevant to NIAMS
because these studies may help explain how human psoriasis is connected to psoriatic arthritis and may reveal
novel therapeutic targets or biomarkers for early or potential arthritic disease.
My long-term goal is to establish an independent research program studying how inflammation remains
localized within epithelial tissues such as the skin. The studies described above will provide an outstanding
starting point as they aim to understand how skin dysregulation can cause joint inflammation. My research
background is primarily in cellular signaling and protein biochemistry. My career development aims are to build
my intellectual and scientific foundation in cellular immunology and develop professional relationships with
rheumatology-focused researchers. I also plan on developing key research skills in epithelial biology as well as
transcriptomic and statistical analysis. These development goals will be pursued with didactic courses along
with participation in seminar series, workshops, and conferences. Together with mentorship from Dr. Averil Ma,
a leading molecular immunologist, and guidance from a multidisciplinary scientific advisory committee of
immunologists, epithelial biologists, and genomics experts, these aims will position me for an independent
research career as a physician-scientist.
Terms: <(TNF)-α><2-dimensional><21+ years old><3-D><3-Dimensional><3D><A20 protein><APF-1><ATP-Dependent Proteolysis Factor 1><Adult><Adult Human><Advisory Committees><Affect><Anatomic Sites><Anatomic structures><Anatomy><Antigens><Arthritis><Automobile Driving><Binding><Binding Proteins><Biology><Body Tissues><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><Cachectin><Cachectin Receptors><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular Immunology><Chronic small plaque psoriasis><Complex><Cutaneous><Cutaneous Disorder><Cytokine Network><Cytokine Network Pathway><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><Data><Defect><Dermatoses><Development><Development Plans><Diagnosis><Digit><Digit structure><Discoid psoriasis><Disease><Disorder><Distal><Dysfunction><Early Diagnosis><Educational workshop><Epidermis><Epithelium><Evolution><Foundations><Functional disorder><Genes><Genetic Polymorphism><Genomics><Germ Lines><Goals><HMG-20><High Mobility Protein 20><Histologic><Histologically><Human><Human Characteristics><Human Nature><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><Immune><Immune infiltrates><Immune signaling><Immunes><Immunoglobulin Enhancer-Binding Protein><Immunologist><Immunology><Inflammation><Inflammatory><Inflammatory Infiltrate><Inflammatory Response><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor><Interleukin 17 Precursor Gene><Interleukin-17><Intracellular Communication and Signaling><Investigators><Joint Diseases><Joints><Knock-in><Knowledge><Leadership><Learning><Ligand Binding Protein><Ligand Binding Protein Gene><Link><Location><Macrophage-Derived TNF><Mentors><Mentorship><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Monocyte-Derived TNF><Mouse Strains><Murine><Mus><NF-kB><NF-kappa B><NF-kappaB><NFKB><NIAMS><National Institute of Arthritis, and Musculoskeletal, and Skin Diseases><Nature><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Nummular psoriasis><Pathogenesis><Pathogenicity><Pathology><Pathway interactions><Patients><Phase><Physicians><Physiopathology><Plaque psoriasis><Play><Population><Position><Positioning Attribute><Predisposition><Process><Protein Binding><Protein Biochemistry><Protein/Amino Acid Biochemistry><Proteins><Psoriasis><Psoriasis Arthropathica><Psoriasis vulgaris><Psoriatic Arthritis><Publishing><Research><Research Personnel><Researchers><Rheumatology><Role><Scientist><Series><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Skin><Skin Diseases><Skin Diseases and Manifestations><Statistical Data Analyses><Statistical Data Analysis><Statistical Data Interpretation><Susceptibility><T-Cells><T-Lymphocyte><TNF><TNF A><TNF Alpha><TNF Receptor Family Protein><TNF Receptor Superfamily><TNF Receptors><TNF gene><TNF-α><TNFA><TNFR><TNFα><Task Forces><Tissues><Transcription Factor NF-kB><Tumor Necrosis Factor><Tumor Necrosis Factor Receptor><Tumor Necrosis Factor Receptor Family><Tumor Necrosis Factor Receptor Superfamily><Tumor Necrosis Factor-alpha><Ubiquitin><United States><Variant><Variation><Workshop><Zinc Finger Domain><Zinc Finger Motifs><Zinc Fingers><adulthood><advisory team><arthritic><arthropathic><arthropathies><arthropathy><biological signal transduction><bound protein><career><career development><conference><convention><cutaneous disease><cytokine><dermal disease><dermal disorder><developmental><driving><early biomarkers><early detection><early detection biomarkers><early detection markers><experiment><experimental research><experimental study><experiments><fascinate><immune cell infiltrate><immunogen><improved><in vivo><inflamed joint><joint degeneration><joint degradation><joint destruction><joint disorder><joint inflammation><joint swelling><joint tissue degeneration><kappa B Enhancer Binding Protein><keratinocyte><keratinocyte differentiation><knockin><mouse model><multidisciplinary><murine model><mutant><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapeutics><new therapy><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapeutics><novel therapy><novel therapy approach><novel therapy target><nuclear factor kappa beta><pathophysiology><pathway><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><polymorphism><prevent><preventing><programs><psoriasiform><psoriatic><skills><skin disorder><social role><statistical analysis><summit><symposia><symposium><therapeutic biomarker><therapeutic marker><three dimensional><thymus derived lymphocyte><transcriptomics><two-dimensional>