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Principal Investigator: Margaret Kathryn Tamburro
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $48,974
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Project Abstract
Tendons can withstand large forces due to a highly aligned, dense collagen matrix. However, their low
cellularity and relative inability to recruit reparative cells post-injury, as well as susceptibility to excessive
scarring, results in loss of tendon structure and mechanical function. Type I collagen (Col1) is the primary
collagen of healthy tendon and type III collagen (Col3) is a minor constituent that increases in response to
injury. Persistently increased Col3 contributes to persistent fibrovascular scarring and structural and functional
deficits in the healing tendon. In perinatal tendons, Col3 is increased, similar to the injured state, compared to
healthy mature tendons. Unlike the healing response, the process of neonatal tendon development yields a
structurally and functionally superior tendon with a highly aligned Col1-dense matrix. Moreover, neonatal
developing tendon demonstrates improved efficiency and quality of healing compared to healing mature
tendon. Understanding the role of Col3 in the developmental and healing processes of the neonatal tendon will
increase our ability to recapitulate tendon development with tissue engineering and improve tendon injury
treatment. Therefore, our overall objective is to delineate the contribution of Col3 to development and healing
in the neonatal tendon through modulation of matrix properties and cellular activity. Specifically, we will test the
hypothesis that Col3 is crucial for early neonatal development but contributes less to regulation of development
at later time points as relative Col3 in the tendon decreases. We also hypothesize that the neonatal tendon has
enhanced capacity for a robust proliferative response to tendon injury which creates a Col3-dense healing
matrix favorable for tendon progenitor migration and differentiation to ultimately deposit aligned, Col1 fibrils
which restore tendon structure and function. To test these hypotheses, we generated a novel, inducible Col3
deficient mouse (i.e. Col3a1F/F) to temporally control Col3 reduction. The study aims are: Aim 1: Define the
temporal dynamics of the regulatory function(s) of Col3 during phases of neonatal tendon development and
Aim 2: Define the regulatory function(s) of Col3 during phases of neonatal healing. Viscoelastic mechanical
testing, transmission electron microscopy, immunohistochemistry, gene expression, proteomics, and 11
integrin analyses will be used to assess the structural, mechanical, and compositional properties of tendons in
both aims. Insights gleaned from this work will be relevant to a variety of conditions that reduce Col3
expression including vascular Ehlers Danlos syndrome, aging, smoking and menopause and will highlight
therapeutic targets for enhancing tendon injury treatment. The proposed work will be carried out in a world-
class training environment at the University of Pennsylvania’s McKay Orthopaedic Research Laboratory. This
environment combined with an expert sponsorship team, including experts in studies of tendon structure and
function as well as matrix biology, will fully support completion of this proposal and facilitate development into a
competent independent investigator capable of producing rigorous and reproducible clinically relevant work.
Terms: <21+ years old><Acceleration><Adult><Adult Human><Aging><Biology><Blood Vessels><Body Tissues><Cell Body><Cell-Extracellular Matrix><Cells><Cellular Infiltration><Cellularity><Characteristics><Cicatrix><Clinical><Collagen><Collagen Fiber><Collagen Fibril><Collagen Type I><Collagen Type III><Cutis Elastica><Deposit><Deposition><Development><Developmental Process><Diameter><Dryness><ECM><Economic Burden><Ehlers-Danlos Disease><Ehlers-Danlos Syndrome><Environment><Extracellular Matrix><Fibroblasts><Foundations><Gene Expression><Generalized Growth><Glean><Growth><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Incidence><Infiltration><Injury><Integrins><Integrins Extracellular Matrix><Investigation><Investigators><Knock-out><Knockout><Laboratory Research><Measures><Mechanics><Menopause><Mice><Mice Mammals><Minor><Modeling><Murine><Mus><Natural regeneration><Neonatal><Orthopedic><Orthopedic Surgical Profession><Orthopedics><Pennsylvania><Perinatal><Peripartum><Phase><Play><Predisposition><Process><Progenitor Cells><Property><Proteomics><Regeneration><Regulation><Reproducibility><Research Personnel><Researchers><Resistance><Role><Scars><Scientific Inquiry><Smoking><Stress><Susceptibility><Tendon Injuries><Tendon structure><Tendons><Testing><Time><Tissue Engineering><Tissue Growth><Tissues><Training><Transmission Electron Microscopy><Type 1 Collagen><Universities><Weight><Work><Wound Repair><adulthood><bioengineered tissue><clinical relevance><clinically relevant><comparative><crosslink><cutis hyperelastica><defined contribution><density><developmental><elastic skin><engineered tissue><fetal><fibrillogenesis><healing><improved><inflammatory environment><inflammatory milieu><injured><injuries><injury response><innovate><innovation><innovative><insight><joint mobility><joint mobilization><joint movement><knock-down><knockdown><mechanic><mechanical><mechanical properties><migration><mouse model><multidisciplinary><murine model><neonatal mice><neonate><novel><ontogeny><post-natal development><postnatal><postnatal development><prenatal><progenitor><progenitor cell differentiation><progenitor cell migration><progenitor differentiation><progenitor migration><recruit><regenerate><regenerative><regenerative approach><regenerative strategy><regenerative technique><resistant><response><response to injury><social role><stem and progenitor differentiation><stem cell differentiation><stem cell migration><stem cells><tendon development><tendon growth><tendon maturation><therapeutic target><unborn><vascular><viscoelasticity><weights><wound healing><wound recovery><wound resolution>