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RISS 인기검색어
- 검색키워드
- 저자 : Alassaf, Nancy Salman Mohammad (검색결과 2 건)
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Pregnancy Associated Plasma Protein-aa Is a Novel Regulator of Neuron Survival
Alassaf, Mroj ProQuest Dissertations & Theses The University of 2021 해외박사(DDOD)
Neuron loss compromises the function of the nervous system and is a hallmark of neurodegenerative disorders. Mitochondria are critically important for cell survival. Despite the diverse etiologies of neurodegenerative disorders, a common underlying feature is mitochondrial dysfunction. Therefore, identification of inherent molecular and genetic mechanisms that regulate mitochondrial function may provide promising therapeutic targets. Through characterization of a zebrafish mutant, we have identified a novel regulator of mitochondrial function and neuron survival: Pregnancy Associated Plasma Protein-aa (Pappaa). pappaa encodes a secreted metalloprotease that stimulates the local availability of insulin-like growth factor 1 (IGF1) by cleaving IGF binding proteins, thereby freeing IGF1 to bind to its receptor. Although IGF1 has been extensively studied within the context of cell survival, little is known about how IGF1 is regulated to promote cell survival, and whether it impacts essential organelle function. My dissertation aims to answer these questions. In chapter 2, we demonstrate that loss of Pappaa causes mitochondrial dysfunction in zebrafish lateral line hair cells. We show that pappaa mutant hair cells have a buildup of mitochondrial calcium and exhibit altered activity. pappaa mutant hair cells also show elevated levels of mitochondrial ROS, suggesting that Pappaa acts to attenuate mitochondria-generated ROS. Furthermore, we show that pappaa mutant hair cells are more vulnerable to pharmacological stimulation of mitochondrial ROS production, supporting the idea that pappaa mutant hair cells are predisposed to ROS-induced death. Exposure to an IGFBP inhibitor improved hair cell survival in pappaa mutants following pharmacological induction of ROS; and conversely, attenuation of IGF1 signaling in wild type larvae reduced hair cell survival. Taken together, our results suggest that Pappaa promotes hair cell survival by regulating mitochondrial function through the IGF1 signaling pathway. In chapter 3, we provide evidence supporting a model by which Pappaa regulates mitochondrial calcium load, and thereby mitochondrial function, by regulating the endoplasmic reticulum (ER)-mitochondria axis. pappaa mutant hair cells showed excessive and abnormally close ER-mitochondria contacts, suggesting enhanced ER-mitochondria calcium transfer. In support of this, pappaa mutant hair cells showed increased vulnerability to pharmacological induction of ER-mediated calcium release. Furthermore, we show that processes downstream of the ER-mitochondria axis are disrupted by Pappaa loss of function. pappaa mutant hair cells show mitochondrial fragmentation and reduced autophagic flux. The ER-mitochondria connection can be altered by ER stress. We show that pappaa mutant hair cells have an active unfolded protein response indicating ER stress. In chapter 4, we reveal that Pappaa is required for motor neuron survival. Pappaa-deficient motor neurons die prematurely. Gene expression analysis revealed upregulation of antioxidants indicating oxidative stress. Treatment with an IGFBP inhibitor rescues motor neuron degeneration in pappaa mutant larvae, suggesting that Pappaa regulates motor neuron survival by stimulating the IGF1 signaling pathway. Overall, work presented in this dissertation uncovers a novel role for Pappaa in promoting neuron survival by regulating the ER-mitochondria connection, mitochondrial function, and oxidative stress.
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Alassaf, Nancy Salman Mohammad Texas A&M University ProQuest Dissertations & Thes 2019 해외박사(DDOD)
This research focuses on overcoming the difficulties of using BIM in conceptual design. It suggests that incorporating formal knowledge with computational concepts within BIM enables the tool to support the conceptual design process. This research used a mixed-methods approach that comprised of historical-interpretive research, model-based inquiry, and quasi-experimental research. First, a computational framework called Architectural Information modeling (AIM) was developed. AIM is a computational design framework that uses BIM to represent a formal language explicitly and provide a generative description of an architectural style. It employs various strategies to define conceptual design vocabularies and syntactical rules. In AIM, a direct connection between the abstract diagram and the actual built form is established. Second, the formal language of Richard Meier was selected as a test case. AIM was used to code the language of the Douglas house and generate the Smith house from the same model. Moreover, various other options that have the same formal language were created using the same model. The notion of stylistic change was explored too. Second, architectural design pedagogy was selected as an area of exploration to validate AIM. A pedagogical framework to teach AIM was developed to conduct a quasi-experimental study in the form of a longitudinal study. At the College of Architecture at Texas A&M University, three second-year design studios (38 students) participated in this intervention study. Data were collected through observations, student survey, student writing assignments, and student projects. Descriptive and inferential statistical methods, content analysis, and a panel of experts were used to analyze the data. The findings of the study illustrate that AIM can provide a shift from BIM as a construction-oriented modeling environment to a design environment where the architect can think, design, and generate multiple design options that incorporate explicit aesthetic and intellectual values. This research has produced significant original contributions in four areas: Building Information Modeling (BIM), the theory of formal language and formal studies in architecture, architectural design education and the role of BIM in design studios, and conducting research through design.
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