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Principal Investigator: John A Collins
Organization: THOMAS JEFFERSON UNIVERSITY
Fiscal Year: 2024
Award: $25,696
Funding agency: National Institute on Aging
PROJECT SUMMARY/ABSTRACT
Age is the number one risk factor for osteoarthritis (OA), however, the mechanisms that drive age-associated
joint changes and how these contribute to cartilage damage are not well defined. As OA joint tissues age, it is
well established that cartilage-forming stem cells (CSCs) display a significant decline in their ability to
differentiate, and the joint environment becomes more inflammatory. Both of these factors together undermine
the ability to recover from injuries and also contributes to the failure of autologous stem cell therapies. Thus, we
propose an innovative dual strategy which will address both. We hypothesize that activation of sirtuin 6 (SIRT6)
will rejuvenate older CSCs, and apoptosis signal regulating kinase 1 (ASK1) inhibition will reestablish a
regenerative environment in the joint. Together, this novel solution has the potential to greatly augment the ability
for CSC differentiation and cartilage repair in the aged population. We will test this hypothesis and determine the
epigenetic mechanisms that SIRT6 regulate in the following three Aims. In Aim 1, we will determine the
mechanisms by which (a) SIRT6 activation and (b) ASK1 inhibition enhance the cartilage-forming differentiation
and pro-survival activities of aged CSCs. In Aim 2, we will determine the efficacy of SIRT6 activation, in the
presence of ASK1 inhibition to stimulate cartilage formation in aged, male and female rodents. Finally, in Aim 3,
we will determine the efficacy of SIRT6 activation and ASK1 inhibition to promote cartilage regeneration and
repair in response to chondral injury in a pre-clinical aged minipig model. These Aims will be achieved through
comprehensive in vitro analysis of young and old (male and female) CSCs and macrophages, in proof-of-concept
aging rodent models (mice and rats), and a clinically relevant large animal chondral defect model (aged minipig).
Importantly, the findings from this proposal are likely to give unique and important insights into the role of
epigenetic regulation of aged cells and the role of the surrounding environment in other aging and diseased
tissues. If successful, the overall impact of this novel pro-regenerative therapy to ameliorate the ravages of aging
and joint injury would represent a significant advancement in the treatment of age-associated diseases, such as
OA. Additionally, it will lead to the discovery of new disease-modifying treatments for other organ systems and
increase the ability of the aged population to live a healthy, mobile life.
Terms: <ASK1 Protein Kinase><Address><Age><Aging><Animals><Apoptosis Signal-Regulating Kinase 1><Autologous><Body System><Body Tissues><Cartilage><Cartilaginous Tissue><Cell Death><Cellular Immune Function><Common Rat Strains><Defect><Degenerative Arthritis><Degenerative polyarthritis><Disease><Disorder><Environment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Failure><Female><In Vitro><Inflammation><Inflammatory><Inhibition of Apoptosis><Injury><Joints><Life><MAP3K5 Protein Kinase><MAP3K5 gene><MAPK Kinase Kinase 5><MAPKKK5><Macrophage><Mice><Mice Mammals><Miniature Swine><Minipigs><Mitogen-Activated Kinase Kinase Kinase Kinase 5><Modeling><Murine><Mus><Mφ><Natural regeneration><Organ System><Osteoarthritis><Osteoarthrosis><Persons><Progenitor Cells><Proteins><Rat><Rats Mammals><Rattus><Regeneration><Rejuvenation><Risk Factors><Rodent><Rodent Model><Rodentia><Rodents Mammals><Role><Silent Mating Type Information Regulator 2-like Proteins><Sir2-like Proteins><Sirtuins><Testing><Tissues><age associated><age associated alterations><age associated changes><age associated disease><age associated disorder><age associated impairment><age correlated><age correlated alterations><age correlated changes><age dependent><age dependent alterations><age dependent changes><age dependent disease><age dependent disorder><age dependent impairment><age linked><age related><age related alterations><age related changes><age related human disease><age specific><age specific alterations><age specific changes><age-related disease><age-related disorder><age-related impairment><aged><aged animal><aged animals><aged group><aged groups><aged individual><aged individuals><aged people><aged person><aged persons><aged population><aged populations><ages><aging population><alterations with age><animal old age><articular cartilage><cartilage regeneration><cartilage repair><cell age><cellular age><changes with age><clinical relevance><clinically relevant><degenerative joint disease><determine efficacy><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><elderly animal><epigenetic regulation><epigenetically><evaluate efficacy><examine efficacy><healing><hypertrophic arthritis><immune function><injuries><innovate><innovation><innovative><insight><joint damage><joint injury><joint trauma><male><mini pig><mini-swine><miniswine><necrocytosis><new approaches><novel><novel approaches><novel strategies><novel strategy><old animals><osteoarthritic><population aging><pre-clinical><preclinical><progenitor cell based therapy><progenitor cell differentiation><progenitor cell therapy><progenitor cell treatment><progenitor differentiation><progenitor therapy><progenitor treatment><regenerate><regeneration based therapy><regeneration therapy><regenerative><regenerative therapeutics><regenerative therapy><regenerative tissue><repair><repaired><response><social role><stem and progenitor cell therapy><stem and progenitor differentiation><stem cell based therapy><stem cell differentiation><stem cell mediated therapy><stem cell therapeutics><stem cell therapy><stem cell treatment><stem cell-based therapeutic><stem cell-based treatment><stem cells>