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Petit Institute Breakfast Club Seminar Series
Petit Institute Breakfast Club Seminar Series
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ItemOsteoimmunology: Exploring the Role of the Immune System in Regulating Bone in Health and Disease(Georgia Institute of Technology, 2013-12-10) Pacifici, RobertoOur laboratory has pioneered the field of osteoimmunology. The laboratory is specialized in conducting in vivo studies in mice treated with PTH or subjected to ovariectomy. We use genetic models, retroviral transduction, bone marrow transplantation, T cell transfer and in vivo treatments with hormones, cytokines and antibodies. Typical end points include sophisticated flow cytometric analysis of bone marrow cells and microCT and histomorphometric analysis of bone structure. The lab is equipped with in vivo and in vitro microCT scanners. We have been the first to recognize that T cells play a pivotal role in the mechanism of action of estrogen and PTH in bone by regulating osteoclast and osteoblast development and function. We have shown that mice lacking T cells are protected against the bone loss induced by estrogen deficiency and hyperparathyroidism. We have has also shown that T cells regulate the number and function of mesenchymal stem cells. We are currently investigating the mechanism by which T cells mediate the expansion of hemopoietic stem cells caused by estrogen deficiency and PTH. Another main focus is to understand why “intermittent” PTH treatment causes bone anabolism while “continuous” PTH treatment causes bone loss. We hypothesize that the response to PTH depends on the effects of this hormone on T cell production of Wnt10b and TNF. A third project involves the use of intravital microscopy to study the effects of estrogen deficiency and PTH on the trafficking of T cells in the bone marrow.
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ItemPrediction and Design in Chemical Evolution(Georgia Institute of Technology, 2013-09-10) Grover, Martha A.Discrete atoms and molecules interact to form macromolecules and even larger mesoscale assemblies, ultimately yielding macroscopic structures and properties. A quantitative relationship between the nanoscale discrete interactions and the macroscale properties is required to design, optimize, and control such systems; yet in many applications, predictive models do not exist or are computationally intractable.
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ItemRegulation of Ryanodine Receptor Calcium Release Channels by Endogenous Effectors(Georgia Institute of Technology, 2013-07-09) Balog, Edward M.Fluctuations in the intracellular calcium (Ca2+) concentration are used to signal numerous cellular events. Impaired cellular Ca2+ regulation can lead to pathology and cell death, thus tight control of intracellular Ca2+ concentration is vital to the survival of all cells. This a particular challenge for cardiac and skeletal muscle cells as they use the controlled release of Ca2+ from the sarcoplasmic reticulum (SR) to initiate skeletal muscle contraction and the heartbeat. Ryanodine receptor (RyR) Ca2+ channels are the efflux pathway for the release of Ca2+ from the SR, however, these channels are not simple conduits for calcium efflux; rather they integrate cellular signals to finely tune Ca2+ release from intracellular stores. The critical role these channels play in muscle function is exemplified by the mutations in the channels that can lead to lethal cardiac arrhythmia or adverse reactions to anesthetics. Further these channel may contribute to muscle weakness associated with skeletal muscle fatigue and aging. A thorough understanding of RyR channel regulation by endogenous effectors is not only critical for our understanding of muscle function but may contribute to the development of therapeutic agents targeting these channels. I will discuss our work on two potential endogenous channel regulators, S-adenosyl-l-methionine (SAM) and calmodulin (CaM) and briefly describe some of our aging work. Physiological concentrations of SAM, the primary methyl group donor for enzyme-mediated methylation, activated the cardiac isoform of the RyR. This effect of SAM was unrelated to its role as a methyl group donor but rather was mediated by a RyR adenine nucleotide-binding site. Interestingly, SAM but not ATP activation was associated with a marked increase in the frequency of channel openings to a sub-conductance level. CaM is a small, ubiquitous protein that contains Ca2+-binding sites in each of its two lobes. Ca2+-free CaM activates the skeletal muscle RyR and Ca2+-bound CaM inhibits the channel. We have identified a CaM Ca2+-binding site required for the conversion of CaM from a RyR activator to a channel inhibitor. By manipulating the Ca2+ affinity of this site, we were able to modify the RyR activation profile. Future goals include defining the molecular characteristics required for adenine nucleotide activation of RyR channels and determining the role of CaM in voltage-activation of skeletal muscle.
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ItemTherapeutic Angiogenesis and Bone Regeneration with Natural and Synthetic Small Molecules(Georgia Institute of Technology, 2013-06-11) Botchwey, Edward A.Endothelial cells play significant roles in conditioning the environment in local tissues after injury by the production and secretion of angiocrine factors. At least two distinct subsets of leukocytes, CD45+ CD11b+ Ly6C+Gr1+CX3CR1lo inflammatory monocytes (IM) and CD45+CD11b+Ly6CGr1-CX3CR1hi anti-inflammatory monocytes (AM), respond differentially to these angiocrine factors and promote pathogen/debris clearance and angiogenesis/wound healing, respectively. Our laboratory is currently investigating how local sphingosine 1-phosphate receptor 3 (S1P3) agonism recruits AM to remodeling vessels. We employ micron and nanoscale biomaterials to deliver FTY720, a S1P1/3 agonist, to inflamed and ischemic tissues, to reduce in pro-inflammatory cytokine secretion and an increase in regenerative cytokine secretion. The altered balance of cytokine secretion results in a reduction in inflammatory monocyte recruitment and an increase in anti-inflammatory CX3CR1hi monocyte recruitment to a pro-regenerative perivascular niche. Increased S1P3 expression and activation on AM resulted in significantly enhanced SDF-1α chemotaxis over IM. AM recruitment also enhanced arteriolar diameter expansion and increased length density of the local vasculature: classic signs of vascular remodeling. This work establishes a role for S1P receptor signaling in the local conditioning of tissues by angiocrine factors that preferentially recruit regenerative monocytes that can enhance healing outcomes, bone tissue regeneration, and biomaterial implant functionality.
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ItemOcular Biomechanics: Lots of Good Problems Looking for Solutions(Georgia Institute of Technology, 2013-04-09) Ethier, C. RossEyes matter – vision loss is consistently rated as one of the most feared disabilities and blindness imposes huge social and economic costs. Good human vision requires, among other processes, biomechanical homeostasis within the eye itself. In this talk I will discuss the role of biomechanics and mechanobiology in several ocular conditions and processes: emmetropia (the development of the eye to achieve a sharp image on the retina), secondary cataract and glaucoma. The emphasis will be on describing open clinical and basic science problems in ocular biomechanics.
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ItemExploring Lymphatic Function: An Engineered Toolbox to Shed Light on Nature’s Invisible Vessels(Georgia Institute of Technology, 2013-01-08) Dixon, J. BrandonProper lymphatic function is essential to a variety of important physiologic processes including immune cell trafficking, lipid absorption, and the regulation of fluid balance. However, the experimental difficulties associated with making actual measurements on lymphatics have slowed our understanding of these processes. In vitro experiments on isolated primary lymphatic endothelial cells or lymphatic muscle cells remove the cell from its native biological and mechanical microenvironment, making the interpretation of results challenging. In vivo experiments, on the other hand, often require highly invasive and terminal procedures to access the vessels. In this talk I will describe several experimental platforms we have developed to assist in both of these issues. By culturing cells in microenvironments that more accurately recreate their biophysical and physiologic surroundings, we seek to not only better recapitulate the in vivo state, but to explore how changes in this mechanical environment participate in the pathogenesis of lymphatic disease. Through the use of NIR imaging techniques, we can perform longitudinal studies on lymphatic function and measure lymphatic pumping pressure in a minimally invasive fashion. Finally, we have developed several approaches using a fluorescently-labeled fatty acid analogue to quantify the dynamics of lipid transport by lymphatics both in vivo and in vitro and have evidence that lymphatic transport of lipid is not the passive process that it has been historically regarded to be.