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Principal Investigator: Grace Ji-eun Shin
Organization: OHIO STATE UNIVERSITY
Fiscal Year: 2024
Award: $182,231
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
PROJECT SUMMARY
My career goal is to lead an independent research group to investigate the pathology and resolution of
pain to solve neuropathic pain problems. To achieve this goal, I propose to develop and use novel translational
strategies to investigate neuron-substrate interactions in the skin layer using a combination of human and animal
models of peripheral sensory neuropathy. My research focuses on a common type of peripheral sensory
neuropathy induced by chemotherapy, which affects over 3 million people in the US alone. While chemotherapy-
induced peripheral neuropathy (CIPN) develops in up to 80% of cancer patients treated with chemotherapeutics,
there are no effective prevention or treatment strategies. Considering the dynamic extracellular environment of
cutaneous sensory nerves and recent understanding that keratinocytes can also function as a nociceptor, it is
vital to understand the maintenance and function of both neurons and keratinocytes to solve neuropathic pain.
Hence, I propose to test the hypothesis that dysregulation of neuron and epidermal interactions underlie
pathological progression of CIPN. Building from my recent work that identified protective roles of integrins in
CIPN, my proposal has three aims that use cutting-edge tools and innovative multi-disciplinary approaches. In
Aim 1, I will investigate neuron-substrate interactions and their regulatory mechanisms in a Drosophila in vivo
CIPN model. I will use genetics and advanced microscopy approaches to label, manipulate, and detect
subcellular changes in neuron to substrate contacts and link with functional changes in a CIPN model. Using
integrins as a model to understand cell surface protein-mediated mechanisms underlying CIPN, I will
characterize endocytic regulators that modulate surface protein expression mediating neuron-substrate contacts.
In Aim 2, I will use human induced pluripotent stem cell (iPSC) technology to identify keratinocyte-nociceptive
neuron interactions and cell-type-specific pathology in a co-culture CIPN model. Given species differences in
sensory neurons, I expect that establishing a human model to investigate the impact of sensory neurons and
extrinsic factors on pathological progression in CIPN will provide critical insights. In Aim 3, I will establish and
validate a 3D human skin-nerve co-culture CIPN model to investigate neuron-substrate relationships and
integrin-mediated protection. Because subtypes of nociceptive neurons target different epidermal layers and
contribute to distinct pathology in peripheral neuropathy, a 3D engineered human skin will be incorporated in the
model. This will allow me to investigate subtype-specific pathology and to resolve nociceptive neuron terminal
degeneration and dysfunction in CIPN. This proposal will provide new insights into pathological progression and
mechanisms mediated by neuron-substrate interactions and a strong foundation for my future research. As my
primary expertise is in neuroscience using Drosophila models, investigating human neurons and epidermal cells
requires new training in skin biology and stem cell biology. The proposed plan will significantly facilitate my career
goal to solve intractable neuropathic pain problems in patients.
Terms: <3-D><3-Dimensional><3D><Acceleration><Affect><Afferent Neurons><Animal Model><Animal Models and Related Studies><Anzatax><Asotax><Assay><Bioassay><Biological Assay><Biology><Bristaxol><Cancer Patient><Cell Body><Cell Surface Proteins><Cell-Extracellular Matrix><Cells><Chemotherapy-induced peripheral neuropathy><Clinic><Clinical Trials><Co-culture><Cocultivation><Coculture><Coculture Techniques><Development><Disease><Disorder><Drosophila><Drosophila genus><Dysfunction><ECM><Engineered skin><Environment><Epidermis><Extracellular Matrix><Foundations><Functional disorder><Genetic><Goals><Hand><Health><Human><Human Engineering><Integrins><Integrins Extracellular Matrix><Intervention><Intervention Strategies><Investigation><Knowledge><Label><Larva><Lead><Link><Maintenance><Mediating><Membrane><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Microscopy><Modeling><Modern Man><Molecular><Monitor><Nerve><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Neuropathy><Neurosciences><Nociception><Nociceptors><PNS Diseases><Paclitaxel><Paclitaxel (Taxol)><Pain><Painful><Pathologic><Pathology><Pathway interactions><Patients><Pb element><Peripheral><Peripheral Nerve Diseases><Peripheral Nerves><Peripheral Nervous System Diseases><Peripheral Nervous System Disorders><Peripheral Neuropathy><Peripheral Sensory Neuropathy><Persons><Phenotype><Physiology><Physiopathology><Praxel><Preventative strategy><Prevention strategy><Preventive strategy><Proteins><Proteomics><Protocol><Protocols documentation><QOL><Quality of life><Recycling><Research><Resolution><Role><Sensory><Sensory Neurons><Skin><Stimulus><Substrate Interaction><Surface><Surface Proteins><Symptoms><Taxol><Taxol A><Taxol Konzentrat><Testing><Therapeutic><Toxic effect><Toxicities><Training><Work><career><cell type><chemotherapy><chemotherapy induced neuropathy><cutaneous sensory nerve><dermal sensory nerve><developmental><extracellular><foot><fruit fly><genetic approach><genetic strategy><hands><heavy metal Pb><heavy metal lead><hiPSC><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><human model><iPS><iPSC><iPSC technology><iPSCs><improved><in vivo><induced human pluripotent stem cells><induced pluripotent cell><induced pluripotent stem cell><induced pluripotent stem cell technology><inducible pluripotent stem cell><innovate><innovation><innovative><insight><interdisciplinary approach><interventional strategy><keratinocyte><membrane structure><model of animal><model of human><multidisciplinary approach><neuronal><neuropathic><neuropathic pain><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><nociceptive><nociceptive neurons><novel><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pain-sensing neurons><pain-sensing sensory neurons><pain-sensing somatosensory neurons><painful neuropathy><pathophysiology><pathway><preservation><progenitor biology><progenitor cell biology><protective effect><protein expression><protein function><receptor recycling><resolutions><response><sensory neuropathy><social role><species difference><stem and progenitor biology><stem cell biology><superresolution microscopy><three dimensional><tool><trafficking><transcriptomics><translation strategy><translational approach><translational strategy><treatment strategy>