[F32] Defining the role of catecholaminergic neurons in wound healing
Ente: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Scadenza: 2028-05-31
Importo max: 76.300 EUR
Paese: US
Descrizione
Project Summary
As the primary barrier between the body and the environment, mammalian skin is highly heterogeneous, and
densely innervated, enabling the sensations of touch, temperature, and pain in response to injury. Post injury,
successful skin regeneration requires the precise spatial and temporal organization of multiple cell types and
their ability to communicate with one another. When these processes are disrupted, the skin fails to regenerate
leading to chronic wound formation. One specific population in which this is often observed is those with
diabetes, with up to 25% of diabetic patients also developing a chronic non-healing wound in their lifetime. In
addition to chronic wounding, diabetes is also associated with neuropathies or nerve damage. Yet, whether
these complications are intertwined or how neurons in the skin may regulate regeneration remains unclear.
Therefore, the overall goal of this proposal is to determine how nerve endings found within the skin contribute
to the wound healing process through intercellular communication in vivo, and how this process goes awry
under diabetic conditions. Skin serves as an excellent model for studying the role of innervation in tissue
regeneration, due to its accessibility for imaging, well defined stages of repair, and availability of genetic mouse
models and tools that allow for targeted manipulation of specific neuronal subsets within it. Recently, our lab
uncovered the unexpected transient role of skin resident neurons during skin injury repair. Robust nerve
bundles are observed within the wound bed as early as 24 hours post injury. However, as healing progresses
and additional cell types infiltrate the damaged area, these nerve bundles are depleted from the regenerating
tissue. Furthermore, pharmacologically depleting the skin of its innervation impairs the wound healing process.
Together, this data suggesting a critical role of skin resident neurons during the skin regeneration. In aim 1, I
will define the class and function of skin resident neurons involved in normal and diabetic wound
repair. Using tissue clearing techniques, whole mount and live imaging, pharmacological approaches to target
specific subtypes of neurons, and various genetic mouse models, I will generate a comprehensive view
neuronal dynamics during wound healing. In aim 2, I will delineate the mechanisms in which neurons
communicate to other cell types in the niche to regulate wound healing. By employing RNA sequencing,
fiber photometry, and in vitro assays, I will identify signaling pathways and secretory factors involved in neuron
mediated wound repair. Together, these studies will provide significant insight into the neuronal populations
involved in skin regeneration and identify potential therapeutic targets for enhancing wound healing in diabetic
patients.
Istituzione: YALE UNIVERSITY
PI: Abigail Mayying Benvie
Progetto: 1F32AR087195-01
Settori: National Institute of Arthritis and Musculoskeletal and Skin Diseases
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