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PHLPP inhibition and Osteoarthritis-Associated Pain

Award Number: R21AR082134
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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PHLPP inhibition and Osteoarthritis-Associated Pain - ABSTRACT Osteoarthritis (OA) is a progressive and debilitating disease characterized by deterioration of articular cartilage and pathologic changes to other tissues leading to joint stiffness and pain. Non-surgical treatments focus on behavior modifications and pain relief, but little is known about the molecular pathways controlling nociception during OA pathogenesis. In this project, we will examine how controlling the activity of PHLPP phosphatases contributes to joint innervation in vivo and neurite extension in vitro. We identified PHLPPs as suppressors of chondrocyte regeneration and pain-related behaviors. PHLPP1 and PHLPP2 are present in human and mouse sensory neurons and abnormally expressed in human OA cartilage. In an animal model of OA, intra-articular injection of PHLPP inhibitors prevented joint hypersensitivity and cartilage degradation and reduced sensory neuron innervation of joint tissues (e.g., subchondral bone, periosteum). PHLPP inhibitors suppressed outgrowth of small/medium sensory neurons and expression of neurotransmitters and neurofilaments in vitro. The goal of this project is to determine the mechanisms by which small molecule inhibitors of PHLPP phosphatases suppress OA-associated pain. The central hypothesis is that PHLPP inhibitors prevent innervation of osteoarthritic joints and alter molecular pathways controlling sensory neurite extension. We will study mechanisms by which PHLPP inhibitors prevent neurite extension and joint pain after knee injury with sensitive murine reporters of innervation and with human iPSC- derived sensory neuron model systems.


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: 2025 ( Subtotal = -$1,214 )
2025	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	5/7/2025	NON-COMPETING CONTINUATION	-$1,214
														Subtotal = -$1,214

Issue Date FY: 2024 ( Subtotal = $169,653 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	12/7/2023	NON-COMPETING CONTINUATION	$157,410
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	8/6/2024	NON-COMPETING CONTINUATION	$12,243
														Subtotal = $169,653

Issue Date FY: 2023 ( Subtotal = $209,880 )
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	1/25/2023	NEW	$209,880
														Subtotal = $209,880

Grand Total All Awards = $378,319

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PHLPP inhibition and Osteoarthritis-Associated Pain

Award Number: R21AR082134

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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