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+ | <span class="header"><a id="Galaxy1_Hamburger1_Burgers_Link_3" href="https://2016.igem.org/Team:Tsinghua/Human_Practices">Human Practices</a></span> | ||
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+ | <li><a id="Galaxy1_Hamburger1_Burgers_Children_3_Link_0" href="https://2016.igem.org/Team:Tsinghua/Human_Practices">Overview</a></li> | ||
+ | <li><a id="Galaxy1_Hamburger1_Burgers_Children_3_Link_1" href="https://2016.igem.org/Team:Tsinghua/Human_Practices#tag_engagement">Public Engagement</a></li> | ||
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+ | <span class="header"><a id="Galaxy1_Hamburger1_Burgers_Link_4" href="https://2016.igem.org/Team:Tsinghua/MedalChecklist">Medal Checklist</a></span> | ||
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+ | <br> | ||
+ | <h1 class="contentPage">modeling</h1> | ||
+ | <br> | ||
+ | We model our system mainly by the following assumptions:<br> | ||
+ | 1. PAMmer and sgRNA of the target gene are abundant, so all the suvCas9 is bound with them;<br> | ||
+ | $$suvCas9 + sgRNA + PAMmer \to suvCas9::sgRNA::PAMmer$$ | ||
+ | <br> | ||
+ | 2. The total concentration of suvCas9 (located in cytoplasm and nucleus) and the target mRNA (normal and mutated) stay the same;<br> | ||
+ | $$[suvCas9::sgRNA::PAMmer(cytosolic)] + [suvCas9::sgRNA::PAMmer(nucleic)] + [mRNA(canonical)::suvCas9::sgRNA::PAMmer(cytosolic)] + [mRNA(mutated)::suvCas9::sgRNA::PAMmer(cytosolic)] = {c}_{0}$$ | ||
+ | $$mRNA(mutated) + mRNA(canonical) = {c}_{R}$$ | ||
− | < | + | <br>3. All the related reactions, which are listed below, obey the steady-state assumption, i. e., they are in the equilibrium state; |
− | </div> | + | $$suvCas9::sgRNA::PAMmer(cytosolic) \to suvCas9::sgRNA::PAMmer(nucleic), {K}_{0}$$ |
+ | $$mRNA(canonical) + suvCas9::sgRNA::PAMmer(cytosolic) \to mRNA(canonical)::suvCas9::sgRNA::PAMmer(cytosolic), {K}_{1}$$ | ||
+ | $$mRNA(mutated) + suvCas9::sgRNA::PAMmer(cytosolic) \to mRNA(mutated)::suvCas9::sgRNA::PAMmer(cytosolic), {K}_{2}$$ | ||
+ | <br>4. After binding with mRNA, the suvCas9 complex cannot enter the nucleus; | ||
+ | Using the above mentioned assumptions, we can know: | ||
+ | $$[suvCas9::sgRNA::PAMmer(nucleic)] = \frac{{K}_{0}}{1 + {K}_{0} + {K}_{1}[mRNA(canonical)] + {K}_{2}[mRNA(mutated)]} \times {c}_{0}......(1)$$ | ||
+ | <br>We also assume: | ||
+ | $$[mRNA(mutated)] = \alpha \times {c}_{R}$$ | ||
+ | $$[mRNA(canonical)] = (1- \alpha) \times {c}_{R}$$ | ||
+ | $${K}_{1} = t \times {K}_{2}, t >> 1$$ | ||
+ | In fact: | ||
+ | $${K}_{0} >> 1$$ | ||
+ | So, the equation (1) can be modified to: | ||
+ | $$[suvCas9::sgRNA::PAMmer(nucleic)] / {c}_{0} = \frac{{K}_{0}}{{K}_{2}{c}_{R}(1 - t)\alpha + {K}_{2}{c}_{R}t + {K}_{0}}......(2)$$ | ||
+ | The equation (2) is plotted below:<br> | ||
+ | <br> | ||
+ | <img src="https://static.igem.org/mediawiki/2016/d/d3/T--Tsinghua--model1.jpeg" style="width:50%;height:50%;margin-left:200px"> | ||
+ | <br> | ||
+ | <br> | ||
+ | The relation between suvCas9::sgRNA::PAMmer(nucleic) and thymidine kinase(TK) expression is linear in the working condition: | ||
+ | $$[TK] = {k}_{0}[suvCas9::sgRNA::PAMmer(nucleic)]......(3)$$ | ||
+ | We assume a sigmoid function between [TK] and probability of cell death: | ||
+ | $$P(cell death) = \frac{1}{1 + e^{-{k}_{1}[TK] + {k}_{2}}}......(4)$$ | ||
+ | Integrating the equation (2), (3) and (4), we get: | ||
+ | $$P(cell death) = \frac{1}{1 + e^{{k}_{2} - {c}_{0}{k}_{0}{k}_{1}\frac{{K}_{0}}{{K}_{2}{c}_{R}(1 - t)\alpha + {K}_{2}{c}_{R}t + {K}_{0}}}}$$ | ||
+ | It can also be written in the logarithm relative risk format: | ||
+ | $$log(\frac{P(cell death)}{1 - P(cell death)}) = {c}_{0}{k}_{0}{k}_{1}\frac{{K}_{0}}{{K}_{2}{c}_{R}(1 - t)\alpha + {K}_{2}{c}_{R}t + {K}_{0}} - {k}_{2}$$ | ||
+ | In this final equation, we can modify several parameters: ${c}_{0}, {k}_{0}$ by the following method: | ||
+ | ${c}_{0}$: By changing the suvCas9 promotor and terminator. | ||
+ | ${k}_{0}$: By changing the inducible promotor of the TK gene | ||
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Latest revision as of 23:43, 19 October 2016