Theses and Dissertations from UMD
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New submissions to the thesis/dissertation collections are added automatically as they are received from the Graduate School. Currently, the Graduate School deposits all theses and dissertations from a given semester after the official graduation date. This means that there may be up to a 4 month delay in the appearance of a give thesis/dissertation in DRUM
More information is available at Theses and Dissertations at University of Maryland Libraries.
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Item LONG-RANGE SIGNALING AT THE INTESTINAL-NEURAL AXIS PROMOTES ORGANISMAL HEME HOMEOSTASIS IN C. ELEGANS(2014) Sinclair, Jason Wallace; Hamza, Iqbal; Animal Sciences; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Metazoans synthesize and regulate intracellular heme in a cell autonomous manner although genetic evidence in vertebrates suggests that cell non-autonomous mechanisms may exist at the organismal level. In C. elegans, a heme auxotroph, extraintestinal tissues are intrinsically dependent on the intestine, which acquires dietary heme for sustenance, supporting the concept that intestinal heme status must be coordinated at the systemic level to regulate whole-organism heme homeostasis. Here we show, by conducting a functional genome-wide RNAi screen in an intestinal-restricted heme sensor worm, that an interorgan heme signaling pathway exists and that >30% of the genes identified from the RNAi screen altered heme homeostasis in the intestine even though these genes are not expressed in the intestine. The biological basis for this signaling is underscored by HRG-7, a cathepsin protease-like protein secreted by the intestine and internalized by distally-located neurons. HRG-7 is specifically secreted from the intestine during heme limitation and hrg-7 depletion causes embryonic lethality concomitant with a heme deficiency response. Reciprocally, neuron-to-intestine heme signaling is mediated by the bone morphogenic protein homolog DBL-1, which recapitulates hrg-7 deficiency when depleted. Remarkably, depletion of both genes simultaneously results in markedly enhanced growth and heme deficiency phenotypes, suggesting that bidirectional signaling between the intestine and neurons mediates systemic heme homeostasis. Our results have uncovered an unexpected role for a protease family member in long-range communication between organs at the intestinal-neural axis to regulate systemic heme homeostasis in metazoa. As humans have over thirty cathepsin and cathepsin-like proteases, several of which are secreted, we anticipate that these proteins may play analogous roles in mammalian biology.Item Distinguishing Modes of Eukaryotic Gradient Sensing(2005-08-25) Skupsky, Ron; Losert, Wolfgang; Nossal, Ralph J; Physics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The behaviors of biological systems depend on complex networks of interactions between large numbers of components. The network of interactions that allows biological cells to detect and respond to external gradients of small molecules with directed movement is an example where many of the relevant components have been identified. This behavior, called chemotaxis, is essential for biological functions ranging from immune response in higher animals to the food gathering and social behavior of ameboid cells. Gradient sensing is the component of this behavior whereby cells transduce the spatio-temporal information in the external stimulus into an internal distribution of molecules that mediate the mechanical and morphological changes necessary for movement. Signaling by membrane lipids, in particular 3' phosphoinositides (3'PIs), is thought to play an important role in this transduction. Key features of the network of interactions that regulates the dynamics of these lipids are coupled positive feedbacks that might lead to response bifurcations and the involvement of molecules that translocate from the cytosol to the membrane, coupling responses at distant point on the cell surface. Both are likely to play important roles in amplifying cellular responses and shaping their qualitative features. To better understand the network of interactions that regulates 3'PI dynamics in gradient sensing, we develop a computational model at an intermediate level of detail. To investigate how the qualitative features of cellular response depend on the structure of this network, we define four variants of our model by adjusting the effectiveness of the included feedback loops and the importance of translocating molecules in response amplification. Simulations of characteristic responses suggest that differences between our model variants are most evident at transitions between efficient gradient detection and failure. Based on these results, we propose criteria to distinguish between possible modes of gradient sensing in real cells, where many biochemical parameters may be unknown. We also identify constraints on parameters required for efficient gradient detection. Finally, our analysis suggests how a cell might transition between responsiveness and non-responsiveness, and between different modes of gradient sensing, by adjusting its biochemical parameters.