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Principal Investigator: TIMOTHY M GRIFFIN
Organization: OKLAHOMA CITY VA MEDICAL CENTER
Fiscal Year: 2023
Funding agency: Veterans Affairs
Osteoarthritis (OA) disproportionately affects veterans, resulting in more pain and functional limitations
compared to the general population. No disease-modifying treatments exist for OA, and current pain
medications (e.g., opioids and NSAIDs) have limited long-term efficacy and adverse side effects. Unresolved
cellular and molecular joint inflammation is recognized as the central mechanism of OA progression. However,
a barrier to progress in the field is identifying the causes of chronic OA inflammation and how to resolve them.
The applicant's long-term goal for overcoming this barrier is to understand the molecular mechanisms of how
exercise therapy reduces OA inflammation and pain so that synergistic drug targets can be identified and
developed for therapeutic use. The premise of this application is that macrophages depend on lipid metabolism
reprogramming to complete anti-inflammatory alternative activation. The objective here is to determine how
intra-articular adipose tissue lipolysis modifies joint inflammation by regulating anti-inflammatory macrophage
polarization. The central hypothesis is that the resolution of joint inflammation requires the temporal coupling of
infra-patellar fat pad (IFP) lipolysis with macrophage lipid uptake and fatty acid metabolism to drive alternative
activation. This hypothesis has been developed based on the applicant's exciting preliminary data showing that
exercise triggers a transient induction of pro-inflammatory cytokines and macrophages in the knee synovium
and IFP, which fully resolves by day 14 of running. Notably, the induction and resolution of inflammation occurs
in parallel with a transient cycle of IFP lipolysis, fibrosis, and lipogenesis. The rationale for the proposed
research is that an understanding of the causal relationship between joint tissue metabolites and cellular
inflammatory mediators has the potential to generate new therapeutic opportunities by advancing fundamental
knowledge about how joint inflammation is regulated. With strong preliminary data and expertise in small
animal exercise, metabolism, and OA studies, the applicant will test the hypothesis by pursuing three specific
aims: 1) Determine how intra-articular adipose tissue lipolysis mediates macrophage activation, joint
inflammation, and post-traumatic OA; 2) Determine the effect of macrophage lipid uptake and fatty acid
oxidation on joint inflammation and the development of post-traumatic OA; and 3) Develop a combined
physical and biologic intervention strategy targeting lipid metabolism to reduce joint inflammation and pain in a
pre-clinical model of chronic knee OA. Aims 1 and 2 will be tested in mouse models of resolving and non-
resolving joint inflammation using wheel running and destabilization of the medial meniscus (DMM) models,
respectively. The models, which have been established as feasible in the applicant's hands, will be used to test
causal mechanisms that establish the pro- or anti-resolving effects of intra-articular lipids on joint inflammation.
In aim 1, these include an inducible genetic approach to block lipolysis in the joint or a pharmacologic
approach to enhance lipolysis. In the second aim, an inducible genetic approach will be used to inhibit
peroxisome proliferator activated receptor-γ (PPARγ) in macrophages or stimulate PPARγ pharmacologically.
The third aim combines physical and PPARγ pharmacologic treatments in the DMM model to test for
synergistic interactions that improve pain and function more than exercise alone. By focusing on the cellular
and molecular transducers of OA exercise therapy, the proposed research tests new, innovative paradigms for
designing drugs to potentiate the therapeutic effects of OA exercise therapy. The proposed research is
significant because it will initiate the systematic study of how synovial joint metabolism may be manipulated to
promote the resolution of joint inflammation. This knowledge is also expected to be important for other OA
therapies, such as optimizing the joint environment to support stem cell and tissue-engineering-based
regenerative medicine strategies.
Terms: <Acute><Address><Adipose tissue><Affect><Agonist><Analgesic Agents><Analgesic Drugs><Analgesic Preparation><Analgesics><Animal Model><Animal Models and Related Studies><Animals><Anodynes><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatories><Antiinflammatory Agents><Antinociceptive Agents><Antinociceptive Drugs><Arthralgia><Avandia><Biological><Biological Response Modifier Therapy><Biological Therapy><Body Tissues><Chronic><Consumption><Coupling><Cumulative Trauma Disorders><D-Glucose><Data><Degenerative Arthritis><Degenerative polyarthritis><Development><Dextrose><Diarthrosis><Disease><Disorder><Drug Design><Drug Targeting><Drugs><Environment><Exercise><Exercise Therapy><Fats><Fatty Acid Metabolism Pathway><Fatty Acids><Fatty Tissue><Fatty acid glycerol esters><Fibrosis><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Gait Analysis><General Population><General Public><Glucose><Glycolysis><Goals><Hand><Health><Histopathology><Image><Impairment><Inflammation><Inflammation Mediators><Inflammatory><Injury><Intermediary Metabolism><Intervention><Intervention Strategies><Joint Pain><Joints><Knee><Knee Osteoarthritis><Knee joint><Knowledge><Lipids><Lipolysis><Macrophage><Macrophage Activation><Measures><Medial Menisci><Medial meniscus structure><Mediating><Medication><Membrana Synovialis Capsulae Articularis><Meniscus Medialis><Metabolic><Metabolic Processes><Metabolism><Methods><Mice><Mice Mammals><Modeling><Molecular><Molecular Target><Murine><Mus><Mφ><NSAIDs><Nociception><Non Steroidal Antiinflammatory Agents><Non-Steroidal Anti-Inflammatory Agents><Nonsteroidal Anti-Inflammatory Agents><Nonsteroidal Antiinflammatory Agents><Nonsteroidal Antiinflammatory Drug><Operative Procedures><Operative Surgical Procedures><Opiates><Opioid><Oral><Osteoarthritis><Osteoarthrosis><Outcome><Overuse Injury><Overuse Syndrome><PPAR gamma><PPAR-g><PPAR-γ><PPARgamma><PPARγ><Pain><Pain Control><Pain Therapy><Pain management><Painful><Peroxisome Proliferative Activated Receptor Gamma><Peroxisome Proliferator-Activated Receptor gamma><Peroxisome Proliferator-Activated Receptor γ><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacological Treatment><Phenotype><Physiatric Procedure><Physical Exercise><Physical Medicine Procedure><Physical Therapeutics><Physical therapy><Physiotherapy><Pre-Clinical Model><Preclinical Models><Production><Regenerative Medicine><Repetition Strain Injury><Repetitive Motion Disorders><Repetitive Strain Injury><Repetitive stress injury><Research><Resolution><Risk><Running><Surgical><Surgical Interventions><Surgical Procedure><Synovia><Synovial Fluid><Synovial Membrane><Synovial joint><Synovium><Testing><Therapeutic Effect><Therapeutic Uses><Thiazolidinedione Receptor><Time><Tissue Engineering><Tissues><Transducers><Trauma><Traumatic Arthritis><Traumatic Arthropathy><Veterans><active duty><active service><adipogenesis><adipose><antiinflammatory><bioengineered tissue><biologic><biological therapeutic><biological treatment><biologically based therapeutics><biotherapeutics><biotherapy><cytokine><degenerative joint disease><developmental><disability><drug/agent><engineered progenitor cells><engineered stem cells><engineered tissue><exercise intervention><fat metabolism><fatty acid metabolism><fatty acid oxidation><flow cytophotometry><functional improvement><functional outcomes><gait examination><genetic approach><genetic strategy><hands><hypertrophic arthritis><imaging><improve function><improved><improved functional outcomes><improved outcome><in vivo><inflamed joint><inflammatory mediator><injuries><injury to meniscus><innovate><innovation><innovative><instrument><interventional strategy><joint inflammation><joint swelling><knee OA><knee joint OA><knee joint osteoarthritis><lipid biosynthesis><lipid metabolism><lipogenesis><mechanical allodynia><meniscus injury><model of animal><mouse genetics><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><nociceptive><non-steroidal anti-inflammatory drugs><non-steroidal antiinflammatory drugs><nonsteroidal anti-inflammatory drugs><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><osteoarthritic><osteoarthritis associated pain><osteoarthritis pain><pain killer><pain medication><pain reliever><pain treatment><painkiller><pharmacologic><physical activity intervention><physical disability><physically disabled><physically handicapped><post-traumatic osteoarthritis><prevent><preventing><repetitive motion injury><resolutions><response><rosiglitazone><side effect><surgery><tissue-repair responses><treadmill><uptake><white adipose tissue><yellow adipose tissue>