NOVEL INSIGHTS INTO CARDIAC LYMPHATICS, GPCR:RAMP INTERACTIONS, AND ADRENOMEDULLIN SIGNALING

The heart is imbued with a vast lymphatic network which is responsible for fluid homeostasis and immune cell trafficking. Disturbances in the forces that regulate microvascular fluid movement can result in myocardial edema, which has pro-fibrotic and pro-inflammatory consequences. The data presented in Part I describes the first murine model of induced myocardial edema from increased coronary sinus pressure, with clinically important and distinctive sex differences. Moreover, the adherens protein VE-cadherin is demonstrated to be essential for the survival of the postnatal cardiac lymphatic network and the maintenance of adult quiescent cardiac lymphatics. Part II dives into cellular pharmacology by uncovering interactions between G-protein coupled receptors (GPCRs) and receptor activity modifying proteins (RAMPs), particularly between the apelin receptor APJ and the chemokine receptor CXCR4. While cellular pharmacology assays of these newly discovered heterodimers display subtle downstream signaling effects, the physiological importance of these interactions remains to be determined. Part III investigates the interaction between the circulating peptide adrenomedullin, important in lymphangiogenesis, pregnancy, and heart failure, and complement factor H (CFH), an essential protein in the alternative complement pathway of the immune system. Previous research has identified adrenomedullin as a binding partner for CFH, with both enhancing the function of the other. Surprisingly, adrenomedullin overexpression phenocopies CFH null mice, bringing into question their interaction, and highlighting the complexity of both signaling pathways in an in vivo model. Overall, this dissertation uncovers novel insights into cardiac lymphatic biology, GPCR:RAMP interactions, and adrenomedullin signaling.Doctor of Philosoph

Multifocal Langerhans Cell Histiocytosis in an Adult

Eosinophilic granuloma (EG) is the most common and benign form of the spectrum of disorders referred to as Langerhans cell histiocytosis (LCH). Langerhans cell histiocytosis is primarily regarded as a pediatric disease, with few adult cases of multifocal EG of bone reported. We report a case of multifocal EG in a 48-year-old woman, who presented with right knee pain. Radiographs showed a small lytic lesion in the medial femoral condyle. Diagnosis was confirmed by ultrasound-guided biopsy. She had had a previous EG lesion excised from her skull. Whole-body bone scan demonstrated a new skull lesion in the right diploic space, which was confirmed by magnetic resonance imaging. The patient underwent curettage, bone grafting, and prophylactic internal fixation of the right distal femur lesion. The skull lesion was treated with repeat craniectomy. Two years later, she developed a new lesion in the right distal femoral metaphysis, which was treated with intralesional corticosteroid injections. Now, more than 1 year later, the patient is pain-free with no evidence of new or recurrent disease. Because multifocal EG is a rare diagnosis in adults, appropriate clinical suspicion, in combination with radiographic findings and histologic examination, is essential for correct diagnosis and treatment

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RAMP3 determines rapid recycling of atypical chemokine receptor-3 for guided angiogenesis.

Receptor-activity-modifying proteins (RAMPs) are single transmembrane-spanning proteins which serve as molecular chaperones and allosteric modulators of G-protein-coupled receptors (GPCRs) and their signaling pathways. Although RAMPs have been previously studied in the context of their effects on Family B GPCRs, the coevolution of RAMPs with many GPCR families suggests an expanded repertoire of potential interactions. Using bioluminescence resonance energy transfer-based and cell-surface expression approaches, we comprehensively screen for RAMP interactions within the chemokine receptor family and identify robust interactions between RAMPs and nearly all chemokine receptors. Most notably, we identify robust RAMP interaction with atypical chemokine receptors (ACKRs), which function to establish chemotactic gradients for directed cell migration. Specifically, RAMP3 association with atypical chemokine receptor 3 (ACKR3) diminishes adrenomedullin (AM) ligand availability without changing G-protein coupling. Instead, RAMP3 is required for the rapid recycling of ACKR3 to the plasma membrane through Rab4-positive vesicles following either AM or SDF-1/CXCL12 binding, thereby enabling formation of dynamic spatiotemporal chemotactic gradients. Consequently, genetic deletion of either ACKR3 or RAMP3 in mice abolishes directed cell migration of retinal angiogenesis. Thus, RAMP association with chemokine receptor family members represents a molecular interaction to control receptor signaling and trafficking properties.This work was supported by NIH Grants RO1-DK099156, RO1-HD060860, and RO1-HL129086 (to K.M.C.); American Heart Association Innovator Award 16IRG27260077 (to K.M.C.); NIH Grant F32-HL134279 (to D.I.M.); American Heart Association Grant 15POST25270006 (to R.B.D.); NIH Grant F31-HL143836 (to N.R.N.); Biotechnology and Biological Sciences Research Council (BBSRC) Grant BB/M00015X/2 (to G.L.); and BBSRC Doctoral Training Partnership Grant BB/JO14540/1 (to M.H.)

Receptive and expressive vocabulary development in children learning English as an additional language : converging evidence from multiple datasets

Children learning English as an additional language (EAL) are a diverse and growing group of pupils in England's schools. Relative to their monolingual (ML) peers, these children tend to show lower receptive and expressive vocabulary knowledge in English, although interpretation of findings is limited by small and heterogeneous samples. In an effort to increase representativeness and power, the present study combined published and unpublished datasets from six cross-sectional and four longitudinal studies investigating the vocabulary development of 434 EAL learners and 342 ML peers (age range: 4;9-11;5) in 42 primary schools. Multilevel modelling confirmed previous findings of significantly lower English vocabulary scores of EAL learners and some degree of convergence in receptive but not expressive knowledge by the end of primary school. Evidence for narrowing of the gap in receptive knowledge was found only in datasets spanning a longer developmental period, hinting at the protracted nature of this convergence