Mathematical modeling and analysis of gene knockout compensation in pancreatic β-cells
Başlık çevirisi mevcut değil.
- Tez No: 523505
- Danışmanlar: Prof. RICHARD BERTRAM
- Tez Türü: Doktora
- Konular: Matematik, Mathematics
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2017
- Dil: İngilizce
- Üniversite: Florida State University
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Belirtilmemiş.
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: 130
Özet
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Özet (Çeviri)
Living systems consist of several complex interacting components. Depending on the complexity of the organism, these components can span from molecules to tissues and organs. Systems biology is the interdisciplinary field of study that uses mathematical and computational tools to describe and investigate the roles these components play in biological systems and the way their interactions result in functionality. The collaborative work between biological and mathematical sciences brings deeper insights into understanding living systems because, even with the recent advancements in technology, it is impossible to acquire all types of empirical data on many living systems. Technical restrictions together with the complexity of the system components usually give rise to this limitation. Hence, this interdisciplinary field of study makes great contributions to both clinical and basic research by solving these complexities and helping to better interpret the acquired data. Besides, biological experiments can be expansive and time consuming. Therefore, testing biological hypotheses with mathematical models can be significantly beneficial. In this regard, mathematical models can be thought as microscopes developed for specific living systems and inexpensive and fast ways of simulating experiments. Insulin secreting pancreatic b-cells are very good examples of such complex systems. Activity of these cells is controlled by extremely complex metabolic and electrophysiological pathways. Therefore, mathematical modeling approaches are proven to be very effective in the study of pancreatic b-cells. Impairments in the activity of these cells lead to impaired insulin secretion, which can have life threatening complications in the body. Thus, understanding the mechanisms underlying b-cell activity and insulin secretion is crucial. Pancreatic b-cells are excitable cells and they produce electrical activity with the ion channels they express in their plasma membranes. In pancreatic b-cells, insulin secretion is regulated through pathways that link cellular metabolism to the membrane potential through ion channels they express in their plasma membranes. In the initiation and modulation of the insulin secretion ATP-sensitive K+ channels (K(ATP) channels) play a significant role by coupling cell metabolism to the membrane potential. Defects in the expression of K(ATP) channels lead to hypoglycemia associated with excessive insulin secretion in humans. However, mice seem to be able to overcome these defects by employing alternative mechanisms. In this dissertation, we investigate the pathological conditions associated with ATP-sensitive K+ channel deficiency in b-cells and, with a systems biology approach, we propose mechanisms through which mice can compensate for these defects. Using mathematical modeling we explain the dynamics of these compensatory mechanisms and make predictions to test their plausibility. We also demonstrate the results of the in vitro experiments performed in accordance with our model predictions. One of the long-term goals of this study is helping to identify possible therapeutic targets for the treatment of the congenital hypoglycemia that results from K(ATP) channel deficiency. The overall aim of this dissertation is using mathematical modeling and analysis techniques to better understand the experimental data on pancreatic b-cells and guide future research by making testable predictions.
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