<p>Models and computer simulations can help us understand the function and operation of BioBrick Parts and Devices. Simulation and modeling are critical engineering skills that can contribute to project design or provide a better understanding of the modeled process. These processes are even more useful and/or informative when real world data are included in the model. This award is for teams who build a model of their system and use it to inform system design or simulate expected behavior before, or in conjunction with, experiments in the wetlab.</p>
<p>To compete for the Best Model prize, select the prize on the <a href="https://competition.igem.org/deliverables/judging-form">judging form</a> and describe your work on this page.</p>
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Integrated Human Practices
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<p>Please see the <a href="https://competition.igem.org/judging/awards">2024 Awards Page</a> for more information.</p>
<p>Proteinopathies are a group of disorders associated with the misfolding, aggregation, and deposition of proteins, leading to loss of functionality and ultimately resulting in cell death. A lot of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease are examples of proteinopathies. Understanding the mechanisms of the proteinopathies is challenging due to the underlying complexity of protein folding, the rich interwebbing of multiple important cellular pathways, and the unique pathophysiology of each disease. Proteins interact with various other macromolecules in the cell such as - other proteins, lipids, and nucleic acids. These interactions usually affect and influence the stability, localization, and function of a protein in its native state. Understanding these networks is essential to deduce which pathways are involved and get affected in proteinopathies.
Proteinopathies also exhibit a broad abstract range of symptoms which seem to overlap with a range of other age related disorders. Disease progression, even amongst patients with the same diagnosis, seem to differ and vary a lot. This heterogeneity complicates the identification of common underlying mechanisms and hence effective therapeutic targets. Several animal models and cell cultures often fail to replicate the complexity and exactitude of human diseases accurately. While these models provide valuable insights and intuition, they may not capture the full spectrum of pathology seen in patients. Unfortunately, many proteinopathies show clinical symptoms only after extensive damage has already occurred, making early diagnosis potentially very challenging. The underlying pathology may already be well-established, hence leaving the clinician with limited therapeutic options.
In 2018, Aptamers were raised on several peptide segments of Tau, one of them being Thr-231; we then proceed to use those same aptamers as our beginner pool to start our process of SELEX. We expect evolving the affinity of our aptamers over randomly phosphorylated Tau-441 using GSK3β, having at least the 231 Threonine site phosphorylated. However, to reduce the scope of uncertainty, we decided to model the pathological Tau using 'phosphomimetics'. In this method, the phosphorylated substrate is substituted by a structurally similar acidic amino acid. By this, we can mimic the physical structure of the phosphorylated compound (which is what the aptamer binding mechanism depends on). However, we still reckon that the aptamers for the p231 Tau might not be completely compatible with our modifications, hence we also plan to run SELEX on them to generate a final pool of specific, affine aptamer for our investigations.
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<h4class="alert-heading">DISCLAIMER</h4>
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We are not claiming to develop a 'cure' or 'therapeutic' for AD, we are just planning to explore the limits of Aptamer technology with the hopes that it can be one day modelled successfully for a therapeutic application. While research on cell lines and mouse models have shown that TPD can be a very promising potential treatment strategy, it is NOT established via human trials. Hence, the possible side effects of such a strategy are not well understood. We are only wishing to expand the global scientific knowledge.
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<pclass="mt-4">We hope to inspire future researchers to use our idea as a template for tackling other proteinopathies and also to expand and build on our core idea.</p>
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<h2>Overview</h2>
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<p>Mathematical models and computer simulations provide a great way to describe the function and operation of Parts and Devices. Synthetic Biology is an engineering discipline, and part of engineering is simulation and modeling to determine the behavior of your design before you build it. Designing and simulating can be iterated many times in a computer before moving to the lab.</p>
