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Principal Investigator: Kirby M. Sherman
Organization: TEXAS A&M UNIVERSITY
Fiscal Year: 2024
Award: $40,194
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Project Summary/Abstract
Down Syndrome (DS) is a common birth defect caused by trisomy of human chromosome 21 (Hsa21). DS leads
to a vast array of clinical abnormalities affecting most systems of the body, including delayed wound healing, and
an increased risk of long bone and vertebral fractures. Previously, this laboratory has shown that DS patients
have low bone turnover leading to decreased bone mineral density and delayed accrual of peak adult bone
mass, and also confirmed the low bone mass phenotype in mouse models of DS. Additionally, it has been
recently reported that COX2/PGE2 expression is impaired in DS human dermal fibroblasts, which could
contribute to the delayed wound healing and increased risk of infections in the DS population. PGE2 and its
receptors are major mediators of inflammation, wound healing, bone formation and bone healing. More
specifically, the PGE2 receptor subunit 2 (EP2, Ptger2) and EP4, have been shown to regulate bone formation,
and play a crucial role in fracture healing, whereas EP3 and EP4 contribute to macrophage recruitment, the
immune response, and lymphangiogenesis in wound healing. However, what is not known is how PGE2
signaling contributes to bone repair and whether low bone accrual in DS impacts bone regeneration. The
overarching objective of this proposal is to characterize bone healing in DS mouse models and determine if
pharmaceutical treatment at different stages during the regenerative process is able to enhance regeneration in
DS. This project will test the hypothesis that bone healing is significantly impaired in DS, and that decreased
bone turnover leads to attenuated bone regeneration. This study will utilize the DS mouse models, Dp16 and
Ts65Dn, that demonstrate the low bone mass phenotype consistent with the low bone mass observed in DS
patients, to investigate de novo bone regeneration after amputation of the terminal phalanx (P3). P3 amputation
is a model of mammalian injury that faithfully triggers a well-defined regenerative sequence of events that initiates
with inflammation followed by bone resorption, wound closure, and de novo bone formation, allowing the
characterization of the entire injury response. Experiments in Aim 1 will seek to characterize P3 regeneration in
the DS mouse models compared to WT littermates to test the hypothesis that bone regeneration is impaired in
DS mouse models. Aim 2 will investigate the early, or lytic, phase of regeneration and determine whether
treatment with a PGE2 receptor (EP3 and EP4) agonist elicits an immune and wound healing response that is
sufficient to enhance regeneration in DS. The proposed studies of de novo bone regeneration will help to close
the gap in knowledge regarding how DS impacts bone healing and repair, and provide insight into how patient
care can be modified to adequately treat bone injuries in the at-risk DS population.
Terms: <21+ years old><Adult><Adult Human><Affect><Agonist><Amputation><Attenuated><Birth Defects><Body System><Body Tissues><Bone Density><Bone Formation><Bone Injury><Bone Mineral Density><Bone Regeneration><Bone Resorption><CAT scan><COX-2><COX2><CT X Ray><CT Xray><CT imaging><CT scan><Cell Communication and Signaling><Cell Signaling><Chromosome 21><Clinical><Computed Tomography><Congenital Abnormality><Congenital Anatomical Abnormality><Congenital Defects><Congenital Deformity><Congenital Malformation><Data><Dermal><Digit><Digit structure><Dinoprostone><Distal><Down's Syndrome><EP4><EP4 receptor><Epididymal Secretory Protein E4><Event><Exhibits><Fibroblasts><Fracture><Fracture Healing><Frequencies><Genetic Diseases><HE4><Harvest><Human><Human Chromosomes><Immune><Immune response><Immunes><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Immunological response><Impaired tissue repair><Impaired wound healing><Impairment><Inflammation><Inflammation Mediators><Inflammatory><Injury><Intracellular Communication and Signaling><Knowledge><Laboratories><Langdon Down syndrome><Length><Live Birth><Lymphangiogeneses><Lymphangiogenesis><Lytic><Lytic Cycle><Lytic Infection><Lytic Phase><Macrophage><Major Epididymis-Specific Protein E4><Mice><Mice Mammals><Modeling><Modern Man><Mongolism><Monitor><Murine><Mus><Mφ><Natural regeneration><Organ System><Osteoclastic Bone Loss><Osteogenesis><PGE Receptors><PGE2><PGE2 Receptors><PGE2 alpha><PGE2alpha><PGHS-2><PHS-2><PTGS2><PTGS2 gene><Patient Care><Patient Care Delivery><Patients><Phalanx><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phase><Phenotype><Play><Population><Process><Prostaglandin E Receptor><Prostaglandin E2><Prostaglandin E2 alpha><Prostaglandin E2alpha><Prostaglandins><Prostanoids><Putative Protease Inhibitor WAP5><Receptor Protein><Regeneration><Regenerative response><Reporting><Research><Risk><Role><Signal Transduction><Signal Transduction Systems><Signaling><Spinal Fractures><Testing><Time><Tissues><Tomodensitometry><Trisomy><Trisomy 21><Ts65Dn><WAP Four-Disulfide Core Domain Protein 2><WAP5><WFDC2><WFDC2 gene><Wound Repair><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><X-ray microtomography><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><Xray microtomography><abnormal tissue repair><adulthood><aged mice><aged mouse><attenuate><attenuates><biological signal transduction><bone><bone fracture><bone fracture healing><bone fracture repair><bone healing><bone health><bone mass><bone repair><bone tissue formation><bone turnover><bone wound healing><care for patients><care of patients><caring for patients><catscan><chromosome 21 trisomy syndrome><computed axial tomography><computer tomography><computerized axial tomography><computerized tomography><congenital acromicria syndrome><dJ461P17.6><delayed wound healing><digit regeneration><elderly mice><experience><experiment><experimental research><experimental study><experiments><fracture repair><fracture risk><genetic condition><genetic disorder><hCOX-2><healing><histologic stains><histological stains><host response><immune system response><immunoresponse><improved><in vivo><infection risk><inflammatory mediator><injuries><injury and repair><injury response><injury to tissue><insight><long bone><male><micro CT><micro computed tomography><microCT><microtomography><morbus Down><mouse Ts65Dn><mouse model><murine model><non-contrast CT><noncontrast CT><noncontrast computed tomography><novel><old mice><osseous wound healing><pharmaceutical><prostanoid receptor EP4><pseudohypertrophic progressive muscular dystrophy><receptor><recruit><regenerate><regenerate bone><regeneration response><regenerative><repair><repaired><response><response to injury><social role><spine fracture><tissue injury><tissue repair><tissue wound><trisomy 21 syndrome><vertebral fracture><wound><wound closure><wound healing><wound recovery><wound resolution><wounding><wounds>