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Molecular Pathways of Pain Generation in Osteoarthritis

Award Number: R01AR060364
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: 02/01/2011
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Molecular Pathways of Pain Generation in Osteoarthritis - Project Summary Osteoarthritis (OA) is the most common form of arthritis, and a major source of chronic pain. No disease- modifying OA drugs are available to patients, and current analgesic approaches fall short of patients’ needs. Nerve growth factor (NGF) has emerged as a promising target for OA pain. Neutralizing antibodies that prevent NGF from binding to its receptor, tropomyosin receptor kinase A (TrkA), have shown strong analgesic effects in clinical trials for OA pain. However, up to 10% of patients treated with anti-NGF developed rapidly progressive OA, necessitating joint replacement. The mechanism of this deleterious effect of NGF blockade on joint integrity is unknown, exposing our ongoing lack of understanding the relationship between joint damage and pain in OA. During the previous funding cycles, we have developed assays, reporter mice, and neuroanatomical and biophysical techniques for monitoring neuronal activity in vivo to assess pain behaviors and underlying neurobiological mechanisms in mouse models of OA. We have uncovered that joint damage in OA is accompanied by extensive anatomical and functional neuronal plasticity of the nociceptive innervation of the knee. We will build on this discovery to test the central hypothesis that the NGF-TrkA axis is essential for the preservation of joint homeostasis in response to joint injury, through neuronal and non-neuronal mechanisms. We will (Aim 1) Determine the spatial and temporal NGF-TrkA “interactome” in the joint. Using reporter mice, single cell RNAseq of the dorsal root ganglia (DRG), RNAscope, and immunohistochemistry, we will detail which cells in the knee and DRG express Ngf and Ntrk1 during progressive experimental OA, in spatiotemporal relationship to neuronal plasticity and joint pathology. We will validate findings in human knee tissues; (Aim 2) Determine the role of the NGF-TrkA axis in promoting neuronal growth in the OA joint, and how this contributes to pain and joint integrity. We will assess if NGF causes neuroplasticity, by injecting it into knees of NaV1.8 reporter mice and assess pain behaviors, joint innervation, and joint integrity (histology and microCT), as well as functional effects on sensory neurons. Advillin-creERT2 mice will be used to delete Nrtrk1 from sensory neurons in adult mice subjected to DMM or PMX surgery; pain, neuroplasticity, and joint damage will be assessed up to 16 weeks; (Aim 3) Explore the role of the NGF-TrkA axis in OA through non-neuronal mechanisms. We will use Ngf-loxp and Ntrk1-loxp mice to conditionally delete Ngf or Ntrka from select non- neuronal cells (myeloid cells, osteoblasts, or chondrocytes). Mice will be subjected to surgery, and OA monitored up to week 8; (Aim 4) Assess the effect of anti-NGF Abs on the OA joint. The role of the NGF-TrkA axis in the whole joint as an organ will be determined by using neutralizing anti-NGF antibodies, either prophylactically (0-8 and 0-16 weeks) or therapeutically (8-16 weeks) after surgery. This approach will clarify how the NGF-TrkA axis operates at the interface between pain and joint damage in OA. Our experiments will also start to address if and how the pain-producing and homeostatic actions of this axis can be dissociated, in order to identify new targets for OA pain.


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 = $534,402 )
2025	2025	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	13	6/26/2025	NON-COMPETING CONTINUATION	$534,402
														Subtotal = $534,402

Issue Date FY: 2024 ( Subtotal = $575,967 )
2024	2024	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	12	6/6/2024	NON-COMPETING CONTINUATION	$575,967
														Subtotal = $575,967

Issue Date FY: 2023 ( Subtotal = $593,780 )
2023	2023	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	5/31/2023	NON-COMPETING CONTINUATION	$593,780
														Subtotal = $593,780

Issue Date FY: 2022 ( Subtotal = $587,842 )
2022	2022	RUSH UNIVERSITY MEDICAL CENTER	1620 W HARRISON ST	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	7/13/2022	NON-COMPETING CONTINUATION	$587,842
														Subtotal = $587,842

Issue Date FY: 2021 ( Subtotal = $585,687 )
2021	2021	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PRKWY	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	9	8/24/2021	COMPETING CONTINUATION	$604,096
2021	2018	RUSH UNIVERSITY MEDICAL CENTER	1620 W HARRISON ST	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	1/30/2021	NON-COMPETING CONTINUATION	-$18,409
														Subtotal = $585,687

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PRKWY	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	8/26/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $340,964 )
2018	2018	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PRKWY	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	7/20/2018	NON-COMPETING CONTINUATION	$340,964
														Subtotal = $340,964

Issue Date FY: 2017 ( Subtotal = $340,964 )
2017	2017	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PRKWY	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	6/28/2017	NON-COMPETING CONTINUATION	$340,964
														Subtotal = $340,964

Issue Date FY: 2016 ( Subtotal = $424,393 )
2016	2016	RUSH-PRESBYTERIAN-ST LUKE`S MEDICAL CENTER	1700 WEST VAN BUREN STREET	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	6/23/2016	NON-COMPETING CONTINUATION	$424,393
														Subtotal = $424,393

Issue Date FY: 2015 ( Subtotal = $636,080 )
2015	2015	RUSH-PRESBYTERIAN-ST LUKE`S MEDICAL CENTER	1700 WEST VAN BUREN STREET	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	8/18/2015	SUPPLEMENT FOR EXPANSION	$289,308
2015	2015	RUSH-PRESBYTERIAN-ST LUKE`S MEDICAL CENTER	1700 WEST VAN BUREN STREET	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	7/15/2015	NON-COMPETING CONTINUATION	$346,772
														Subtotal = $636,080

Issue Date FY: 2014 ( Subtotal = $343,384 )
2014	2014	RUSH-PRESBYTERIAN-ST LUKE`S MEDICAL CENTER	1700 WEST VAN BUREN STREET	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	8/29/2014	COMPETING CONTINUATION	$343,384
														Subtotal = $343,384

Issue Date FY: 2013 ( Subtotal = $320,625 )
2013	2013	RUSH-PRESBYTERIAN-ST LUKE`S MEDICAL CENTER	1700 WEST VAN BUREN STREET	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	1/17/2013	NON-COMPETING CONTINUATION	$303,750
2013	2013	RUSH-PRESBYTERIAN-ST LUKE`S MEDICAL CENTER	1700 WEST VAN BUREN STREET	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	7/12/2013	NON-COMPETING CONTINUATION	$16,875
														Subtotal = $320,625

Issue Date FY: 2012 ( Subtotal = $337,500 )
2012	2012	RUSH-PRESBYTERIAN-ST LUKE`S MEDICAL CENTER	1700 WEST VAN BUREN STREET	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	3/7/2012	NON-COMPETING CONTINUATION	$337,500
														Subtotal = $337,500

Issue Date FY: 2011 ( Subtotal = $335,250 )
2011	2011	RUSH-PRESBYTERIAN-ST LUKE`S MEDICAL CENTER	1700 WEST VAN BUREN STREET	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	1/21/2011	NEW	$335,250
														Subtotal = $335,250

Grand Total All Awards = $5,956,838

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Molecular Pathways of Pain Generation in Osteoarthritis

Award Number: R01AR060364

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: 02/01/2011

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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