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Mapping PHLPP-Driven Mechanisms of Pain and Pathogenesis in Post-Traumatic Osteoarthritis

Award Number: K99AR086961
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/09/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Mapping PHLPP-Driven Mechanisms of Pain and Pathogenesis in Post-Traumatic Osteoarthritis - Project Abstract Post-traumatic osteoarthritis (PTOA) is a common, progressive and debilitating disease that poses a major socio- economic burden in the US. No disease-modifying medications exist despite persistent pain in nearly half of patients and surgical risks. PTOA is characterized by pathological changes in many joint tissues. Articular cartilage deterioration, subchondral bone sclerosis, and sensory nerve innervation can cause joint stiffness and pain. PH domain leucine-rich repeat protein phosphatases (PHLPPs) are suppressors of chondrocyte regeneration and pain-related behaviors. Intra-articular injection of PHLPP inhibitors (PHLPPi) or deletion of Phlpp1 prevents joint hypersensitivity and cartilage degradation in a model of PTOA. Preliminary data show that Phlpp inhibition suppresses outgrowth of small/medium sensory neurons and expression of neurotransmitters and neurofilaments in vitro as well as subchondral bone innervation in vivo in mice. The research proposed under this training period will explore how Phlpp1 inhibition reduces PTOA-associated pain behaviors. The long- term goal is to define mechanisms by which Phlpp1 contributes to OA pain, guiding the development of targeted pain-relief strategies. My central hypothesis is that Phlpp1 promotes OA pain by altering signaling cascades in pain-producing cells during OA progression. In Aim 1, I will assess how Phlpp1 loss prevents joint pain by quantifying neurite innervation and vascular sprouting using NaV1.8;tdTomato reporter mice and by applying high-resolution spatial transcriptomics of knee joints at early and late PTOA stages to map downstream signaling changes linked to pain behaviors and subchondral bone innervation. In Aim 2, I will conditionally delete Phlpp1 in osteoclasts during DMM-induced PTOA and measure pain behaviors, cartilage damage, and molecular changes in injured joints. The research training, career development, and mentorship plan outlined here will support my goal of becoming an independent investigator in musculoskeletal pain research. During the K99 phase, I will receive primary mentorship from Dr. Jennifer Westendorf and complementary expertise from advisory committee members in pain neuroscience, osteoclast biology, advanced imaging, and spatial transcriptomics. Additional co-mentorship from Dr. Susan Moeschler, a clinical pain expert, will strengthen the translational relevance of my work. Structured training in grant writing, communication, leadership, and mentoring will support my transition to independence during the R00 phase. The Mayo Clinic offers an exceptional environment with extensive institutional resources in musculoskeletal biology, imaging, spatial transcriptomics, behavioral phenotyping, computational analysis, and translational research. Together, this environment and mentoring team will provide the interdisciplinary training and support needed to achieve my career goals.


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: 2026 ( Subtotal = $211,196 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/9/2026	NEW	$211,196
														Subtotal = $211,196

Grand Total All Awards = $211,196

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Mapping PHLPP-Driven Mechanisms of Pain and Pathogenesis in Post-Traumatic Osteoarthritis

Award Number: K99AR086961

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/09/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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