Person: Cahill, Catherine
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Cahill
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Catherine
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Cahill, Catherine
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Publication The Role of T Cells in Osteoporosis, an Update(e-Century Publishing, 2009-05-20) Zhao, Wen; Liu, Yuying; Cahill, Catherine; Yang, Wenlu; Rogers, Jack; Huang, XudongEmerging evidence highlights the importance of the interplay between the bone and immune systems. That evidence bolsters a longstanding recognition that estrogen deficiency, infection, inflammation, and autoimmune disorders are associated with systemic and local bone loss. Yet, only recently has an understanding emerged that T lymphocytes and their products act as key regulators of osteoclast formation, life span, and activity. This review presents this understanding of the process of T lymphocytes and their products mediating osteoporosis and explores some of the most recent findings and hypotheses to explain their action in bone. A more complete appreciation of the interactions between immune and bone cells should lead to targeted therapeutic strategies for diseases that affect either or both systems.Publication Novel Treatments for Airway Disease(Massachusetts Medical Society, 2017-08-10) Cahill, Catherine; Boyce, Joshua; Israel, ElliotPublication Novel 5′ Untranslated Region Directed Blockers of Iron-Regulatory Protein-1 Dependent Amyloid Precursor Protein Translation: Implications for Down Syndrome and Alzheimer's Disease(Public Library of Science, 2013) Bandyopadhyay, Sanghamitra; Cahill, Catherine; Balleidier, Amelie; Huang, Conan; Lahiri, Debomoy K.; Huang, Xudong; Rogers, JackWe reported that iron influx drives the translational expression of the neuronal amyloid precursor protein (APP), which has a role in iron efflux. This is via a classic release of repressor interaction of APP mRNA with iron-regulatory protein-1 (IRP1) whereas IRP2 controls the mRNAs encoding the L- and H-subunits of the iron storage protein, ferritin. Here, we identified thirteen potent APP translation blockers that acted selectively towards the uniquely configured iron-responsive element (IRE) RNA stem loop in the 5′ untranslated region (UTR) of APP mRNA. These agents were 10-fold less inhibitory of 5′UTR sequences of the related prion protein (PrP) mRNA. Western blotting confirmed that the ‘ninth’ small molecule in the series selectively reduced neural APP production in SH-SY5Y cells at picomolar concentrations without affecting viability or the expression of α-synuclein and ferritin. APP blocker-9 (JTR-009), a benzimidazole, reduced the production of toxic Aβ in SH-SY5Y neuronal cells to a greater extent than other well tolerated APP 5′UTR-directed translation blockers, including posiphen, that were shown to limit amyloid burden in mouse models of Alzheimer's disease (AD). RNA binding assays demonstrated that JTR-009 operated by preventing IRP1 from binding to the IRE in APP mRNA, while maintaining IRP1 interaction with the H-ferritin IRE RNA stem loop. Thus, JTR-009 constitutively repressed translation driven by APP 5′UTR sequences. Calcein staining showed that JTR-009 did not indirectly change iron uptake in neuronal cells suggesting a direct interaction with the APP 5′UTR. These studies provide key data to develop small molecules that selectively reduce neural APP and Aβ production at 10-fold lower concentrations than related previously characterized translation blockers. Our data evidenced a novel therapeutic strategy of potential impact for people with trisomy of the APP gene on chromosome 21, which is a phenotype long associated with Down syndrome (DS) that can also cause familial Alzheimer's disease.