Browsing by Author "Orr, Ashley L."

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    A pilot study of the utility of a hospital-based school program for pediatric patients with cardiac diagnoses
    (Frontiers Media, 2024-12-11) Thibodaux, Lia K.; Orr, Ashley L.; Reisinger, Debra L.; Fodstad, Jill; Xu, Guang; Wikel, Kristin; Curtin, Michelle; Psychiatry, School of Medicine
    Introduction: Pediatric patients with complex cardiac diagnoses are at increased risk for physical, cognitive, and developmental complications. Formalized school support [i.e., individualized education programs (IEPs), Section 504 Accommodation Plans (Section 504 Plans)] that addresses the needs of these patients is necessary, and hospital-based school programs (HBSPs) have the potential to bolster the acquisition of academic support. In this pilot study, we look at the impact of one such HBSP. Methods: Retrospective demographic and school support data for pediatric cardiac patients were analyzed. Results: Our sample included 29 pediatric cardiac patients spanning two academic years. These patients had 100 HBSP encounters and 82 inpatient and 12 outpatient encounters, with 68.9% of patients having multiple encounters in a single year and 44.8% of patients being seen in both years. The HBSP made recommendations for patients to receive IEPs (N = 8) and Section 504 Plans (N = 13). The patients also submitted requests for medical homebound(N = 27), obtaining releases of information (N = 39), submitting medical reports (N = 10), and completing certificates of incapacity (N = 7). Statistical analyses revealed no significant relationships with patients entering or receiving a recommendation for an IEP or Section 504 Plan in any of their encounters with the HBSP on the basis of sex, race/ethnicity, school level, or rates of encounters in this sample. Discussion: Similar to previous studies, these patients had high rates of IEPs/Section 504 Plans in place and continued to receive school recommendations through the HBSP. A high use of the HBSP was seen in the total number of encounters and communications (i.e., submitting to the school of record requests for classroom placement changes via medical homebound). Working with the HBSP provided access to information, formal support recommendations, and communication between medical and school settings in the form of changes in school status.
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    Conditional Loss of Nmp4 in Mesenchymal Stem Progenitor Cells Enhances PTH-Induced Bone Formation
    (Oxford University Press, 2023) Atkinson, Emily G.; Adaway, Michele; Horan, Daniel J.; Korff, Crystal; Klunk, Angela; Orr, Ashley L.; Ratz, Katherine; Bellido, Teresita; Plotkin, Lilian I.; Robling, Alexander G.; Bidwell, Joseph P.; Anatomy, Cell Biology and Physiology, School of Medicine
    Activation of bone anabolic pathways is a fruitful approach for treating severe osteoporosis. Yet, FDA-approved osteoanabolics, e.g., parathyroid hormone (PTH), have limited efficacy. Improving their potency is a promising strategy for maximizing bone anabolic output. Nmp4 (Nuclear Matrix Protein 4) global knockout mice, exhibit enhanced PTH-induced increases in trabecular bone but display no overt baseline skeletal phenotype. Nmp4 is expressed in all tissues; therefore, to determine which cell type is responsible for driving the beneficial effects of Nmp4 inhibition, we conditionally removed this gene from cells at distinct stages of osteogenic differentiation. Nmp4-floxed (Nmp4fl/fl) mice were crossed with mice bearing one of three Cre drivers including (i) Prx1Cre+ to remove Nmp4 from mesenchymal stem/progenitor cells (MSPCs) in long bones; (ii) BglapCre+ targeting mature osteoblasts and (iii) Dmp1Cre+ to disable Nmp4 in osteocytes. Virgin female Cre+ and Cre− mice (10wks of age) were sorted into cohorts by weight and genotype. Mice were administered daily injections of either human PTH 1–34 at 30μg/kg, or vehicle for 4wks or 7wks. Skeletal response was assessed using dual-energy X-ray absorptiometry, microcomputed tomography, bone histomorphometry and serum analysis for remodeling markers. Nmp4fl/fl;Prx1Cre+ mice virtually phenocopied the global Nmp4−/− skeleton in the femur, i.e., a mild baseline phenotype but significantly enhanced PTH-induced increase in femur trabecular bone volume/total volume (BV/TV) compared to their Nmp4fl/fl;Prx1Cre− controls. This was not observed in the spine, where Prrx1 is not expressed. Heightened response to PTH was coincident with enhanced bone formation. Conditional loss of Nmp4 from the mature osteoblasts (Nmp4fl/fl;BglapCre+) failed to increase BV/TV or enhance PTH response. However, conditional disabling of Nmp4 in osteocytes (Nmp4fl/fl;Dmp1Cre+) increased BV/TV without boosting response to hormone under our experimental regimen. We conclude that Nmp4−/− Prx1-expressing MSPCs drive the improved response to PTH therapy, and that this gene has stage-specific effects on osteoanabolism.
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    Examining the Role of Hypothalamus-Derived Neuromedin-U (NMU) in Bone Remodeling of Rats
    (MDPI, 2023-03-31) Born-Evers, Gabriella; Orr, Ashley L.; Hulsey, Elizabeth Q.; Squire, Maria E.; Hum, Julia M.; Plotkin, Lilian; Sampson, Catherine; Hommel, Jonathan; Lowery, Jonathan W.; Anatomy, Cell Biology and Physiology, School of Medicine
    Global loss of the neuropeptide Neuromedin-U (NMU) is associated with increased bone formation and high bone mass in male and female mice by twelve weeks of age, suggesting that NMU suppresses osteoblast differentiation and/or activity in vivo. NMU is highly expressed in numerous anatomical locations including the skeleton and the hypothalamus. This raises the possibility that NMU exerts indirect effects on bone remodeling from an extra-skeletal location such as the brain. Thus, in the present study we used microinjection to deliver viruses carrying short-hairpin RNA designed to knockdown Nmu expression in the hypothalamus of 8-week-old male rats and evaluated the effects on bone mass in the peripheral skeleton. Quantitative RT-PCR confirmed approximately 92% knockdown of Nmu in the hypothalamus. However, after six weeks, micro computed tomography on tibiae from Nmu-knockdown rats demonstrated no significant change in trabecular or cortical bone mass as compared to controls. These findings are corroborated by histomorphometric analyses which indicate no differences in osteoblast or osteoclast parameters between controls and Nmu-knockdown samples. Collectively, these data suggest that hypothalamus-derived NMU does not regulate bone remodeling in the postnatal skeleton. Future studies are necessary to delineate the direct versus indirect effects of NMU on bone remodeling.
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    NMUR1 in the NMU-Mediated Regulation of Bone Remodeling
    (MDPI, 2021-09-29) Hsiao, Yu-Tin; Manikowski, Kelli J.; Snyder, Samantha; Griffin, Nicole; Orr, Ashley L.; Hulsey, Elizabeth Q.; Born-Evers, Gabriella; Zukosky, Tara; Squire, Maria E.; Hum, Julia M.; Metzger, Corinne E.; Allen, Matthew R.; Lowery, Jonathan W.; Anatomy, Cell Biology and Physiology, School of Medicine
    Neuromedin-U (NMU) is an evolutionarily conserved peptide that regulates varying physiologic effects including blood pressure, stress and allergic responses, metabolic and feeding behavior, pain perception, and neuroendocrine functions. Recently, several lines of investigation implicate NMU in regulating bone remodeling. For instance, global loss of NMU expression in male and female mice leads to high bone mass due to elevated bone formation rate with no alteration in bone resorption rate or observable defect in skeletal patterning. Additionally, NMU treatment regulates the activity of osteoblasts in vitro. The downstream pathway utilized by NMU to carry out these effects is unknown as NMU signals via two G-protein-coupled receptors (GPCRs), NMU receptor 1 (NMUR1), and NMU receptor 2 (NMUR2), and both are expressed in the postnatal skeleton. Here, we sought to address this open question and build a better understanding of the downstream pathway utilized by NMU. Our approach involved the knockdown of Nmur1 in MC3T3-E1 cells in vitro and a global knockout of Nmur1 in vivo. We detail specific cell signaling events (e.g., mTOR phosphorylation) that are deficient in the absence of NMUR1 expression yet trabecular bone volume in femora and tibiae of 12-week-old male Nmur1 knockout mice are unchanged, compared to controls. These results suggest that NMUR1 is required for NMU-dependent signaling in MC3T3-E1 cells, but it is not required for the NMU-mediated effects on bone remodeling in vivo. Future studies examining the role of NMUR2 are required to determine the downstream pathway utilized by NMU to regulate bone remodeling in vivo.
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    The Notch pathway regulates the bone gain induced by PTH anabolic signaling
    (Wiley, 2022) Delgado-Calle, Jesus; McAndrews, Kevin; Wu, Gerald; Orr, Ashley L.; Ferrari, Adam; Tu, Xiaolin; Srinivasan, Venkatesan; Roodman, G. David; Ebetino, Frank H.; Boeckman, Robert K., Jr.; Bellido, Teresita; Anatomy, Cell Biology and Physiology, School of Medicine
    Parathyroid hormone (PTH) signaling downstream of the PTH 1 receptor (Pth1r) results in both bone anabolic and catabolic actions by mechanisms not yet fully understood. In this study, we show that Pth1r signaling upregulates the expression of several components of the Notch pathway and that Notch signals contribute to the catabolic actions of PTH in bone. We found that constitutive genetic activation of PTH receptor signaling in osteocytes (caPth1rOt ) or treatment with PTH daily increased the expression of several Notch ligands/receptors in bone. In contrast, sustained elevation of endogenous PTH did not change Notch components expression. Deletion of the PTH receptor or sclerostin overexpression in osteocytes abolished Notch increases by PTH. Further, deleting the canonical Notch transcription factor Rbpjk in osteocytes decreased bone mass and increased resorption and Rankl expression in caPth1rOt mice. Moreover, pharmacological bone-targeted Notch inhibition potentiated the bone mass gain induced by intermittent PTH by reducing bone resorption and preserving bone formation. Thus, Notch activation lies downstream of anabolic signaling driven by PTH actions in osteocytes, and Notch pharmacological inhibition maximizes the bone anabolic effects of PTH.