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Principal Investigator: Andrew C White
Organization: CORNELL UNIVERSITY
Fiscal Year: 2024
Award: $320,034
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
PROJECT SUMMARY / ABSTRACT
Melanocyte stem cells (McSCs) of the hair follicle can serve as a reservoir for melanocyte replenishment
to the epidermal layer of the skin. This property has been demonstrated in patients with the depigmentation
disease vitiligo, in which new pigmentation is found in a peri-follicular pattern surrounding hair follicles, following
treatment with narrow-band ultraviolet B radiation (UVB). Unfortunately, repigmentation through UVB therapy is
neither widespread nor durable. On the other hand, McSCs harboring mutations can serve as cells of origin for
melanoma, the deadliest of skin cancers. Melanoma in this context can be initiated by the activation of McSCs
in response to UVB exposure. It is our long-term goal to identify the molecular mechanisms through which UVB
alters the activation and migration of McSCs to ultimately provide a significant impact leading to the improvement
of vitiligo treatment and new methods of melanoma prevention.
Our preliminary data indicate that a pro-inflammatory state in the skin, induced by UVB exposure,
facilitates McSC translocation to the epidermis and melanoma initiation from mutant McSCs. We have also
shown that loss of function in the architectural chromatin remodeling factor Hmga2 results in impairment of both
McSC translocation and melanoma initiation through a cell extrinsic mechanism. The underlying molecular
events through which inflammation and Hmga2 regulate these processes have not been identified. TNF
signaling and neutrophil/macrophage recruitment have been determined as potential mediators of McSC
proliferation and migration, and melanoma initiation from McSCs. It is the central hypothesis of this proposal
that UVB-mediated McSC translocation, and melanoma initiation from McSCs, requires inflammatory cell influx
and TNF signaling, which is induced by tissue-specific Hmga2 transcriptional regulation.
In this proposal, we will test whether specific cell populations and signaling pathways are responsible for
UVB-mediated McSC translocation and melanoma initiation via Aim 1) directed at the necessity of inflammation
mediated recruitment of neutrophils and macrophages, Aim 2) directed at the necessity and sufficiency of
cytokine signaling mediated by Tnf-alpha, and Aim 3) directed at defining the cell population and downstream
transcription changes dependent upon Hmga2. Our approach will utilize our innovative model system to define
these processes in vivo, using deletion/overexpression by cell specific genetic manipulation, antibody and small
molecule neutralization of cell populations and signaling pathways, and transcriptomic profiling on isolated cell
populations. Understanding and conclusively defining the cell populations and transcriptomic changes occurring
during UVB-mediated McSC translocation and melanoma initiation will lead to testing of novel strategies for
vitiligo treatment and melanoma prevention. These goals are directly in line with the mission at NIAMS to
improve the health of patients suffering from skin diseases.
Terms: <(TNF)-α><Antibodies><Architecture><Biologic Models><Biological Models><Biology><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Body Tissues><Cachectin><Cell Body><Cell Communication and Signaling><Cell Isolation><Cell Locomotion><Cell Migration><Cell Movement><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cells><Cellular Migration><Cellular Motility><Chromatin Remodeling Complex><Chromatin Remodeling Factor><Cutaneous><Cutaneous Disorder><Cytokine Signal Transduction><Cytokine Signaling><DNA Damage><DNA Injury><Data><Dependence><Dermatoses><Development><Disease><Disorder><Engineering / Architecture><Epidermis><Event><Gene Transcription><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Goals><Hair Follicle><Hair follicle structure><Health><Human><Immunology><Impairment><Inflammation><Inflammatory><Intracellular Communication and Signaling><Knowledge><Lesion><Macrophage><Macrophage-Derived TNF><Malignant Melanoma><Malignant Skin Neoplasm><Marrow Neutrophil><Mediating><Mediator><Melanins><Melanoma><Melanoma Tumor><Methods><Microbiology><Mission><Model System><Modern Man><Mole the mammal><Molecular><Moles><Monocyte-Derived TNF><Motility><Mutation><Mφ><NIAMS><National Institute of Arthritis, and Musculoskeletal, and Skin Diseases><Neutrophil Infiltration><Neutrophil Recruitment><Neutrophilic Granulocyte><Neutrophilic Infiltrate><Neutrophilic Leukocyte><Patients><Pattern><Pigmentation><Pigmentation physiologic function><Pigments><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Prevention><Process><Progenitor Cells><Property><Public Health><RNA Expression><Radiation exposure><Radiation therapy><Radiotherapeutics><Radiotherapy><Reporting><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Skin><Skin Cancer><Skin Diseases><Skin Diseases and Manifestations><Source><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Tissues><Transcription><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Tumor growth in melanoma><UV irradiated><UV irradiation><UVB><UVB induced><UVB radiation><Ultraviolet B><Ultraviolet B Radiation><Vitiligo><Work><biological signal transduction><cell behavior><cell motility><cell sorting><cell type><cellular behavior><chromatin modifier><cutaneous disease><dermal disease><dermal disorder><developmental><experience><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><genome mutation><improved><in vivo><innovate><innovation><innovative><irradiation><loss of function><malignant skin tumor><melanocyte><migration><mutant><neutrophil><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><overexpress><overexpression><pigment><pigmentations><progenitor biology><progenitor cell biology><progenitor cell migration><progenitor cell population><progenitor cell proliferation><progenitor migration><progenitor population><progenitor proliferation><radiation treatment><recruit><response><skin disorder><small molecule><stem and progenitor biology><stem and progenitor cell population><stem and progenitor cell proliferation><stem cell biology><stem cell migration><stem cell population><stem cell proliferation><stem cells><transcriptome profiling><transcriptomic profiling><transcriptomics><treatment with radiation><tumor><tumor initiation><tumorigenic><ultra violet B radiation><ultra violet irradiation><ultraviolet B induced><ultraviolet b radiation induced><ultraviolet irradiation><ultraviolet light b induced>