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Principal Investigator: Siqi Liu
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $239,197
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
PROJECT SUMMARY/ABSTRACT
Skin has a remarkable ability to heal wounds through re-epithelialization, a repair process fueled by
adult stem cells residing in the epidermis and hair follicles. Following injury, wound-edge
keratinocytes proliferate and migrate to initiate wound closure, which is accompanied by activation
and infiltration of immune cells. My long-term goal is to elucidate the cellular and molecular basis
underlying wound re-epithelialization, how the immune system regulates this process, and how it
affects tissue regeneration. Previously we found activation of the transcription factor Stat3 in
keratinocytes controls many important aspects of wound re-epithelialization, including basal
keratinocyte proliferation, migration and crosstalk with epidermal dendritic T cells (DETCs). However,
the molecular mechanism by which wounding triggers Stat3-mediated re-epithelialization and
activates the immune system remains unclear and is the subject of this study. Cellular injury is
known to produce damage associated molecular patterns (DAMPs) that are sensed by the innate
immune system for host protection. We hypothesize that DAMPs produced by skin wounds are
sensed by innate immune pattern recognition receptors (PRRs), which then signal to produce
cytokines, and further activate Stat3 for wound re-epithelialization. Using a candidate approach and
Stat3 activation as a readout, we will first identify, characterize, and verify wound-edge cytokines that
influence wound re-epithelialization through epidermal-specific genetic knockouts, gene-expression
analysis, and genetic modulation of immune signaling (Aim 1). Next, we describe strategies to
identify the immune signaling pathway, upstream PRR, and the cells responsible for the PRR
signaling through genetic and biochemical approaches (Aim 2). Finally, we describe an inducible
genetic model of wound injury, characterize its similarity to physical wounding, and identify wound-
induced ligands using biochemical purification and an in vitro assay (Aim 3). These lines of
investigation will 1) offer novel insights into the molecular mechanism of wound initiation and innate
immune contribution to skin re-epithelialization, 2) contribute new tools and models to the study of
immune regulation and skin repair, and 3) improve our understanding and therapeutic options for
autoimmune/autoinflammatory skin conditions and diseases associated with poor wound repair. With
an exceptional mentoring team led by Dr. Elaine Fuchs (with Drs. Jean-Laurent Casanova and Daniel
Mucida) and a supportive, stimulating training environment at the Rockefeller University, I am ideally
positioned to fully develop my technical skills and knowledge in skin biology and immunology. My
research, training, and career development will allow me to establish a unique niche in the field of
wound-repair and tissue regeneration as an independent investigator.
Terms: <Affect><Aging><Atopic Dermatitis><Atopic Eczema><Atopic Neurodermatitis><Autoimmune><Basal Transcription Factor><Basal transcription factor genes><Biochemical><Biology><Body Tissues><Carcinoma><Cell Body><Cell Communication and Signaling><Cell Death><Cell Signaling><Cell membrane><Cells><Cellular injury><Chronic><Complex><Cytoplasmic Membrane><Diabetic wound><Disease><Disorder><Disseminated Neurodermatitis><Environment><Epidermis><Epithelial cancer><Epithelium><Event><Family><Gamma-delta T cells><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><General Transcription Factor Gene><General Transcription Factors><Genetic><Genetic Models><Goals><Growth Agents><Growth Factor><Growth Substances><Hair Follicle><Hair follicle structure><Host Defense><Immune><Immune infiltrates><Immune signaling><Immune system><Immunes><Immunology><Immunomodulation><Injury><Innate Immune System><Intracellular Communication and Signaling><Investigation><Investigators><Knock-out><Knockout><Knowledge><Ligands><Malignant Epithelial Neoplasms><Malignant Epithelial Tumors><Mechanics><Mediating><Mentors><Methods><Modeling><Molecular><Necrosis><Necrotic><Outcome><Pathology><Pattern><Pattern recognition receptor><Plasma Membrane><Position><Positioning Attribute><Process><Production><Proliferating><Proteins Growth Factors><Psoriasis><Receptor Signaling><Research><Research Personnel><Researchers><Role><Signal Induction><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Skin><Skin repair><Study Subject><T-Cells><T-Lymphocyte><Technical Expertise><Therapeutic><Tissues><Training><Transcript Expression Analyses><Transcript Expression Analysis><Transcription Activation><Transcription Factor Proto-Oncogene><Transcription factor genes><Transcriptional Activation><Trauma><Universities><Wound Repair><adaptive immunity><adult progenitor><adult stem cell><allergic dermatitis><allergic eczema><analyze gene expression><autoinflammatory><biological signal transduction><career development><cell damage><cell injury><cellular damage><cutaneous repair><cutaneous wound><cytokine><damage to cells><dermal repair><dermal wound><diabetes ulcer><diabetic skin wound><diabetic ulcer><epithelial carcinoma><gene expression analysis><gene expression assay><immune cell infiltrate><immune modulation><immune regulation><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><improved><in vitro Assay><in vivo><injured><injuries><injury to cells><innate immune sensing><insight><keratinocyte><mechanic><mechanical><migration><necrocytosis><non-healing wounds><nonhealing wounds><novel><pathogen><persistent wounds><plasmalemma><psoriasiform><psoriatic><re-epithelialization><recruit><regenerate new tissue><regenerate tissue><regenerating damaged tissue><regenerating tissue><repair><repaired><response><skin wound><social role><somatic progenitor><somatic stem cell><technical skills><thymus derived lymphocyte><tissue regeneration><tissue regrowth><tissue renewal><tissue specific regeneration><tissue wound><tool><transcription factor><transcriptional profiling><wound><wound closure><wound healing><wound injury><wound recovery><wound resolution><wounding><wounds><γδ T cells><γδT cells>