Atopic dermatitis is an inflammatory skin condition that affects an estimated 30% of the US population, mostly children and adolescents. Atopic dermatitis is characterized by chronically itchy skin that can weep clear fluid when scratched, and patients with atopic dermatitis are susceptible to bacterial, viral and fungal skin infection. There currently are no effective treatments for the chronic itch other than temporary symptomatic relief with topical applications (e.g. corticosteroids), and specific neurological pathways associated with the generation of chronic itch have not been elucidated. Here, we propose that CHRONIC ITCH, as occurs in Atopic Dermatitis, involves a novel signaling pathway that ends in release of NPPB by specific neurons in the DRG. Central to this pathway leading to chronic itch are four molecules: a) thymic stromal lymphopoietin (TSLP); b) PERIOSTIN c) the (?v?3) integrin receptor on specific neurons of the DRG called transient receptor potential vanniloid-1 (TRPV1) neurons; and, as described above, d) natriuretic polypeptide precursor b (NPPB). The Specific Hypothesis to be addressed is propagation of chronic itch is is initiated by a Th2 type immune response in the skin related to atopic dermatitis. This causes localized release of the cytokine TSLP from skin keratinocytes (and perhaps other cell types in the skin) which then, in an autocrine/paracrine fashion, binds to these and other keratinocytes via the keratinocyte TSLP/IL7R-receptor complex. This binding activates the JAK-STAT pathway in the keratinocytes, leading to production and release of the protein PERIOSTIN. PERIOSTIN, released by these keratinocytes, then sets in motion the following itch circuit: Released PERIOSTIN binds to a PERIOSTIN - binding integrin receptor ?v?3 expressed on a subset of neurons in the dorsal root ganglia, called TRPV1 neurons. As a result of PERIOSTIN binding, these TRPV1 neurons then release the neuropeptide NPPB centrally in the spinal cord that in response sends itch signals to the brain. We will test this hypothesis through the following specific aims:
Aim 1). To determine if TSLP binding to the specific TSLP receptor complex on keratinocytes provokes production and release of periostin through activation of the JAK-STAT pathway in these cells;
Aim 2) To determine whether PERIOSTIN binds directly to the integrin receptor ?v?3 on TRPV1 neurons (NPPB/SST) in the DRG, and whether this generates an itch sensation in vivo;
Aim 3) To demonstrate that the PERIOSTIN ? integrin receptor ?v?3 on TRPV1 neurons NPPB circuit results in chronic itch in vivo. This proposed research will identify fundamental mechanisms for neuronal responses during the generation of chronic itch secondary to inflammatory skin disease. PERIOSTIN, integrin receptor signaling, and/or NPPB ? producing neurons may provide novel therapeutic targets to treat skin diseases manifested by chronic itch.
Chronic itch associated with inflammatory skin diseases such as atopic dermatitis, can become both physiologically and psychologically debilitating and impart serious clinical consequences. We will study how an endogenous ligand that releases in the skin and then sets in motion the following itch circuit by binding to integrin receptor expressed in the dorsal root ganglia neurons, called TRPV1 neurons, as a result, to propagate the sensation of chronic itch by releasing neuropeptide NPPB in the spinal cord. Our proposed research will identify a molecular pathway involved in cutaneous-nerve responses in the dissemination of chronic itch and may provide potentially open new therapeutic targets for prospective treatment for chronic itch associated with atopic dermatitis.
