Thursday, November 21, 2024 11/21/2024

Integrin receptor: A connecting link between skin and peripheral sensing neurons in atopic dermatitis

Award Number: R01AR077692
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary 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 (αvβ3) 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 αvβ3 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 αvβ3 on TRPV1 neurons (NPPB/SST) in the DRG, and whether this generates an itch sensation in vivo; Aim 3) To demonstrate a direct role of PERIOSTIN and neuropeptide NPPB in the generation of 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $324,368 )
2024	2024	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	7/15/2024	NON-COMPETING CONTINUATION	$324,368
														Subtotal = $324,368

Issue Date FY: 2023 ( Subtotal = $338,732 )
2023	2023	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27607	WAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	6/21/2023	NON-COMPETING CONTINUATION	$338,732
														Subtotal = $338,732

Issue Date FY: 2022 ( Subtotal = $340,344 )
2022	2022	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27607	WAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	6/20/2022	NON-COMPETING CONTINUATION	$212,636
2022	2021	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27607	WAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	10/26/2021	NEW	$127,708
														Subtotal = $340,344

Issue Date FY: 2021 ( Subtotal = $334,400 )
2021	2021	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27607	WAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/29/2021	NEW	$334,400
														Subtotal = $334,400

Grand Total All Awards = $1,337,844

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Integrin receptor: A connecting link between skin and peripheral sensing neurons in atopic dermatitis

Award Number: R01AR077692

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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