Wednesday, January 15, 2025 1/15/2025

Targeting PHLPP to treat interval disc degeneration using surgical and drug delivery methods

Award Number: R01AR078908
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 The rapid increase in painful intervertebral disc (IVD) degeneration (IDD) makes it an urgent need to develop solutions for delaying IDD progression. IDD is associated with chronic inflammation, loss of IVD cellularity, matrix degradation and apoptosis, which are accelerated by dephosphorylation of AKT, PKC, and MAPK signaling pathways. We present preliminary evidence that the phosphatase Pleckstrin homology domain leucine-rich repeat protein phosphatase 1 (PHLPP1) promotes IDD. Thus global deletion of PHLPP1 repressed IDD progression in old mice by preventing matrix degradation and reducing pro-inflammatory cytokine expression. Our preliminary data on degenerated human NP cells suggested that pro-inflammatory responses were decreased after treatment with a small molecule PHLPP inhibitor. We previously developed injectable, nanoformulations that are capable of delivering small molecules at constant rates over an extended period of time. Based on these findings, our preliminary proof of concept and feasibility as well as our recent publication, we propose to test the novel hypothesis that NP compartment specific inhibition of PHLPP1 will delay disease progression via suppressing inflammation and matrix degradation in age-induced spontaneous IDD. Aim 1 will identify the role of PHLPP1 on IDD in the NP compartment in vivo using a model of age-induced spontaneous IDD in conditional Phlpp1 knockout mice. Phlpp1 will be depleted in NP (NPcKO) and the role of Phlpp1 will be assessed with immunohistochemical, molecular, and biomechanical methods. In vitro studies will evaluate the differentially regulated pathways by single cell RNA-sequencing and molecular-biological analysis of mouse NPcKO as well as PHLPP1 knockdown in human NP cells. Aim 2 will test the efficacy of a small molecule PHLPP inhibitor to decelerate IDD by developing an injectable nanoformulation for long-term PHLPP inhibitor release and evaluate its efficacy in a mouse model of spontaneous IDD. This project is highly significant because discogenic backpain is a major burden in the United States. New insights in mechanisms and minimal invasive treatments of IDD will combine mechanistic and translational studies. This study is innovative because the development of a small molecule PHLPP inhibitor has not been previously described and the use of NIR labeled nanoformulations for controlled PHLPP inhibitor delivery to treat IDD is a technical innovation. Successful completion of this study will provide new insights into NP compartment specific progression of IDD and advance small molecule PHLPP inhibitor laden nanoformulation injection as a potential disease-modifying treatment for IDD in humans.


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 = $382,876 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	6/6/2024	NON-COMPETING CONTINUATION	$27,632
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	4/16/2024	NON-COMPETING CONTINUATION	$355,244
														Subtotal = $382,876

Issue Date FY: 2023 ( Subtotal = $396,162 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	5/16/2023	NON-COMPETING CONTINUATION	$396,162
														Subtotal = $396,162

Issue Date FY: 2022 ( Subtotal = $408,772 )
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	5/10/2022	NEW	$408,772
														Subtotal = $408,772

Grand Total All Awards = $1,187,810

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Targeting PHLPP to treat interval disc degeneration using surgical and drug delivery methods

Award Number: R01AR078908

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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