Mapping the joint-nerve interactome of the knee
Ended Cooperative Agreement Awarded Last action
- Award ID
- UC2AR082186
- Recipient
-
Rush University Medical Center UEI C155UU2TXCP3
- Awarding agency
-
National Insititue of Arthritis and Musculoskeletal and Skin Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $40,959,410
Award facts
- Assistance listing
- 93.279 Drug Use and Addiction Research Programs
- Completion date
- Funding
-
- $34,326,318.00 Federal
- $6,633,092.00 Non-federal
- Funding agency
- National Institute of Neurological Disorders and Stroke National Institutes of Health, Department of Health and Human Services
- Place of performance
- Illinois, USA
Award details come from USAspending.gov.
Description
- Abstract
- Our multidisciplinary team assembles basic and translational researchers with expertise in joint biology and neuroscience, proposing a holistic approach to mapping the sensory innervation of murine and human knee joints. We will use state-of-the-art imaging techniques, combined with transcriptomics to construct 3D models of the sensory innervation of the knee, compose a cell atlas in which knee afferents are transcriptionally profiled at a single cell resolution, and document the nerve-joint cell interactome at the transcriptional level. Our overarching objective is to precisely describe the sensory innervation of the knee, and the dynamic changes occurring with aging, joint injury, and osteoarthritis (OA). This will provide the consortium with a rich anatomical and molecular resource to study mechanisms underlying joint pain and guide the development of novel analgesic strategies. Aim 1. Documenting the sensory innervation of the healthy and diseased mouse knee: anatomical and molecular perspectives. Using fluorescent reporter mice to label nociceptors, C-fiber subsets, and proprioceptors, we will map the anatomical innervation of the mouse knee in (a) naïve mice of different ages; (B) after joint injury; (C) in surgically induced OA. We will use ribbon scanning confocal and clearing-enabled lightsheet microscopy to construct high-resolution 3-D anatomical models of joint innervation. We will backlabel knee-innervating afferents and use spatial transcriptomics to describe their molecular phenotypes compared to other non-knee innervating DRG neurons. Aim 2. Documenting the sensory innervation of the healthy and diseased human knee: anatomical and molecular perspectives. We will use a unique set of post mortem knee/DRG samples from (1) healthy knees, age 20-40 (N=15/SEX); (2) knees from donors over 70 (N=15/SEX), in which we anticipate 80-90% to exhibit OA pathology. Knee tissues will be collected in a standardized fashion, including synovium, osteochondral plugs (medial tibial plateau), meniscus, ACL, FAT pad, and quadriceps muscle. In each tissue, we will perform (1) histopathology; (2) IHC for sensory innervation; (3) bulk and scrnaseq; (4) spatial transcriptomics. Matched drgs will be used for bulk rnaseq to identify differentially expressed genes (DEG) between the groups provide information for ligand-receptor analysis. Aim 3. Identifying mediators in the knee synovium that drive disease- associated neuroplasticity. (1) we will reconstruct the cellular interactome between synovial cells and DRG neurons in mouse models of aging, joint injury, and OA using scrnaseq of matched synovium and DRG samples. (2) we will compare patient reports of OA knee pain at the time of TKR to matched synovial histology, including extent of lining hyperplasia, single-cell transcriptional changes, and innervation. Overall, this project will provide the community with comprehensive databases of the neuro-articular environment, which can be mined to (1) undertake mechanistic studies to inhibit pathological neuroplasticity and (2) identify and test new druggable targets. This strategy will pave the way for the development of novel, targeted, non-addictive, and safe analgesic therapeutics for the treatment of joint pain.
Transactions
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| Amendment | $1,223,463 | $0 | |
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| Amendment | $6,633,092 | $0 | |
| Amendment | $6,633,092 | $6,633,092 | |
| Original award | $6,633,092 | $0 |
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Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| New York Society For The Relief Of Ruptured & Crippled, Maintaining The Hospital For Special Surgery | $83,970 | |
| The Rockefeller University | $906,109 | |
| Northwestern University | $103,741 | |
| Regents Of The University Of Michigan | $329,504 | |
| The Hospital For Special Surgery Fund, Inc. | $184,303 | |
| Scripps Research Institute | $836,575 | |
| The Hospital For Special Surgery Fund, Inc. | $83,970 | |
| The Hospital For Special Surgery Fund, Inc. | $77,546 | |
| University Of Texas At Dallas | $350,487 | |
| Scripps Research Institute | $595,504 | |
| The Rockefeller University | $737,585 | |
| Regents Of The University Of Michigan | $693,866 | |
| Northwestern University | $267,759 | |
| Scripps Research Institute | $3,037,314 |
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Quick answers
Who received award UC2AR082186?
UC2AR082186 was awarded to Rush University Medical Center by National Insititue of Arthritis and Musculoskeletal and Skin Diseases (National Institutes of Health) on September 23, 2022.
How much is award UC2AR082186 worth?
$40,959,410 has been obligated on UC2AR082186: $34,326,318 in federal funding and $6,633,092 in non-federal funding.
Which agency awarded UC2AR082186?
National Insititue of Arthritis and Musculoskeletal and Skin Diseases (National Institutes of Health) awarded UC2AR082186, with funding from National Institute of Neurological Disorders and Stroke (National Institutes of Health).
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