Team:Evry/Modeltr1

From 2013.igem.org

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<h2>Introduction</h2>
<h2>Introduction</h2>
<p>
<p>
-
In the very beginning of the project, we focused on the duodenum and the iron absorbed by it. In order to determine if a flush treatment strategy was viable, we first had to model the behaviour of the duodenum regarding iron absorption.
+
In the very beginning of the project, we focused on iron absorption by the duodenum. We first had to model the behaviour of the duodenum regarding iron absorption to determine if a flush treatment strategy was viable.
</p>
</p>
<h2>Observations</h2>
<h2>Observations</h2>
<p>
<p>
-
60% of iron absorption takes place in the duodenum, the last 40% in the jejunum. The duodenum is located in the upper intestines, right after the stomach, and is usually 300mm long.
+
We know that 60% of iron is absorbed in the duodenum and 40% in the jejunum. The duodenum is located in the upper intestines, right after the stomach, and is usually 300mm long.
<br/>
<br/>
 +
A healthy person absorbs about 10% (1-2mg a day) of the daily iron uptake, while a hemochromatosic patient's absorption varies between 50% and 100% of the daily iron uptake<sup><a href="#Ref">[1]</a></sup>.
 +
</p>
 +
 +
<div align="center">
 +
<a id="Fig1"></a>
<div class="captionedPicture" style="width:60%;">
<div class="captionedPicture" style="width:60%;">
   <a title="Absorption" href="https://static.igem.org/mediawiki/2013/3/37/Regulation.png">
   <a title="Absorption" href="https://static.igem.org/mediawiki/2013/3/37/Regulation.png">
Line 25: Line 30:
   </div>
   </div>
</div>
</div>
-
<br/>
+
</div>
-
 
+
<p>
-
A healthy person absorbs about 10% (2mg a day) of the daily iron uptake, while a hemochromatosis person's absorption varies between 50% and 100% of the daily iron uptake<sup><a href="#Ref">[1]</a></sup>.
+
Iron absorption is normally regulated by the liver through hepcidin production (depicted in <a href="#Fig1">Figure 1</a>). This means that after a certain delay, iron absorption eventually reaches a stationary phase.
</p>
</p>
Line 33: Line 38:
<h2>Goals</h2>
<h2>Goals</h2>
<p>
<p>
-
Our goal in this part of the model is to create a generic duodenal iron absorption model so that:
+
We wanted to build a generic duodenal iron absorption model so that:
<ul>
<ul>
<li>We can have a realistic base for the <a href="https://2013.igem.org/Team:Evry/Modeltr2">Final flush treatment model</a></li>
<li>We can have a realistic base for the <a href="https://2013.igem.org/Team:Evry/Modeltr2">Final flush treatment model</a></li>
-
<li>The model can can be reused in the future</li>
+
<li>The model can can be reused in the future for any similar model of absorption.</li>
</ul>
</ul>
</p>
</p>
Line 43: Line 48:
<h2>Assumptions</h2>
<h2>Assumptions</h2>
<ul>
<ul>
-
<li>Our bacteria don't settle in the duodenum</li>
+
<li>Our bacteria doesn't settle in the duodenum</li>
-
<li>No regulation in the patient's iron absorption</li>
+
<li>No regulation of the patient's iron absorption</li>
-
<li>Constant iron flow</li>
+
<li>Constant iron flow in the duodenum lumen </li>
<li>Homogeneous fluid</li>
<li>Homogeneous fluid</li>
<li>The bacterial quantity is constant</li>  
<li>The bacterial quantity is constant</li>  
Line 55: Line 60:
<p>
<p>
This model simulates the digestion process of <b>one meal</b> from the duodenum's point of view.<br/>
This model simulates the digestion process of <b>one meal</b> from the duodenum's point of view.<br/>
-
The duodenum is considered as a cylinder in which a homogeneous fluid flows. So, this model is divided into three steps: the filling of duodenum, the steady state flowing step and the emptying. <br/>
+
The duodenum is considered as a cylinder in which a homogeneous fluid flows. The model is divided into three steps: the filling of duodenum, the steady state flowing step and the emptying. <br/>
-
This model has two variables : the iron disolved in the middle (<b><span style="color:#FF0000;">S</span></b>) and the absorbed iron (<b><span style="color:#0000FF;">A</span></b>). <br/>
+
This model has two variables : the iron dissolved in the duodenum lumen (<b><span style="color:#FF0000;">S</span></b>) and the absorbed iron (<b><span style="color:#0000FF;">A</span></b>). <br/>
We considered the chyme arrives in the duodenum at a constant rate. <b><span style="color:#FF0000;">S</span></b> has a linear component <b>Sp</b> which represents the pulses. The also are an emptying component and an absorption component.<br/>
We considered the chyme arrives in the duodenum at a constant rate. <b><span style="color:#FF0000;">S</span></b> has a linear component <b>Sp</b> which represents the pulses. The also are an emptying component and an absorption component.<br/>
We assumed a linear absorption and a negative feedback regulation for A.
We assumed a linear absorption and a negative feedback regulation for A.
</p>
</p>
 +
<p>
<p>
-
Finally:<br/>
+
<b>Finally:</b><br/>
-
<img src="https://static.igem.org/mediawiki/2013/8/82/Healthyeq.png" width=15% />
+
<table width="100%">
 +
 
 +
<td width="30%">
 +
<img src="https://static.igem.org/mediawiki/2013/8/82/Healthyeq.png" width=80% />
</p>
</p>
 +
</td>
 +
 +
<td width="70%">
<p>
<p>
-
<table width="100%" border="1" style="border-collapse:collapse;">
+
<table width="50%" border="1" style="border-collapse:collapse;">
<tr>
<tr>
<td><b>Name</b></td>
<td><b>Name</b></td>
<td><b>Unit</b></td>
<td><b>Unit</b></td>
<td><b>Description</b></td>
<td><b>Description</b></td>
-
<td><b>Reference</b></td>
 
</tr>
</tr>
 +
<tr>
<tr>
-
<td>Sp</td>
+
<td>A</td>
 +
<td>mg</td>
 +
<td>Absorbed Iron</td>
 +
</tr>
 +
 
 +
<tr>
 +
<td>S</td>
 +
<td>mg</td>
 +
<td>Iron in Duodenum</td>
 +
</tr>
 +
 
 +
<tr>
 +
<td>S<sub>p</sub></td>
<td>mol.s<sup>-1</sup></td>
<td>mol.s<sup>-1</sup></td>
<td>Iron pulse</td>
<td>Iron pulse</td>
-
<td><a href="#Ref">[1][2]</a></td>
 
</tr>
</tr>
<tr>
<tr>
<td>v</td>
<td>v</td>
<td>m.s<sup>-1</sup></td>
<td>m.s<sup>-1</sup></td>
-
<td>Chyme's flow average speed</td>
+
<td>Chyme's flow</td>
-
<td><a href="#Ref">[2]</a></td>
+
</tr>
</tr>
<tr>
<tr>
Line 88: Line 110:
<td>m</td>
<td>m</td>
<td>Duodenum length</td>
<td>Duodenum length</td>
-
<td><a href="#Ref">[3]</a></td>
 
</tr>
</tr>
<tr>
<tr>
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<td>s<sup>-1</sup></td>
<td>s<sup>-1</sup></td>
<td>Duodenum absorption rate</td>
<td>Duodenum absorption rate</td>
-
<td>tuned</td>
 
</tr>
</tr>
<tr>
<tr>
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<td>s<sup>-1</sup></td>
<td>s<sup>-1</sup></td>
<td>Regulation coefficient</td>
<td>Regulation coefficient</td>
-
<td>tuned</td>
 
</tr>
</tr>
</table><br/>
</table><br/>
</p>
</p>
 +
</td>
 +
</table>
 +
 +
<a id="Par"></a>
<h2>Parameters tuning :</h2>
<h2>Parameters tuning :</h2>
<p>
<p>
-
As the iron absorption process greatly differs from an individual to an other, α and σ cannot be found in the litterature. We thus had to tune those parameters.<br/>
+
As the iron absorption process greatly differs from an individual to an other, α and σ cannot be related with anything in the litterature. We thus had to tune those parameters.<br/>
First of all, we know that a hemochromatosic patient absorbs at least 50% of the iron he ingests. Thus, we tuned α to fit this information while assessing σ = 0 (Hemochromatosis : no regulation in iron absorbtion).<br/>
First of all, we know that a hemochromatosic patient absorbs at least 50% of the iron he ingests. Thus, we tuned α to fit this information while assessing σ = 0 (Hemochromatosis : no regulation in iron absorbtion).<br/>
Then, since we know that a healthy person absorbs 10% of the ingested iron, we were able to tune σ.
Then, since we know that a healthy person absorbs 10% of the ingested iron, we were able to tune σ.
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<h2>Results</h2>
<h2>Results</h2>
<p>
<p>
-
These curves represent the total absorbed iron (in red) and the instant iron quantity in the middle (blue).<br/>
+
These curves represent the total absorbed iron (in red) and the instant iron quantity in the duodenum lumen (blue).<br/>
The green line is a landmark: it represents the iron absorption of a healthy person during an average meal.
The green line is a landmark: it represents the iron absorption of a healthy person during an average meal.
</p>
</p>
<p>
<p>
 +
 +
<div align="center">
<a id="Fig2"></a>
<a id="Fig2"></a>
<div class="captionedPicture" style="width:100%;">
<div class="captionedPicture" style="width:100%;">
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   </div>
   </div>
  </div>
  </div>
 +
</div>
 +
The <a href="#Fig2">Figure 2</a> represents what would normally happen during an average meal. It will be a sample graph for our model.<br/>
The <a href="#Fig2">Figure 2</a> represents what would normally happen during an average meal. It will be a sample graph for our model.<br/>
</p>
</p>
<br/>
<br/>
<p>
<p>
 +
 +
<div align="center">
<a id="Fig3"></a>
<a id="Fig3"></a>
<div class="captionedPicture" style="width:100%;">
<div class="captionedPicture" style="width:100%;">
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   </div>
   </div>
  </div>
  </div>
-
The <a href="#Fig3">Figure 3</a> was generated with the same equations as the <a href="#Fig2">Figure 2</a>, but where <b>σ = 0</b>, which means that there is no regulation of iron absorption. <br/>
+
</div>
 +
 
 +
<p>The <a href="#Fig3">Figure 3</a> was generated with the same equations as the <a href="#Fig2">Figure 2</a>, but where <b>σ = 0</b>, which means that there is no regulation of iron absorption.
 +
</p>
 +
 
 +
<h2>Parameter values</h2>
 +
<p>
 +
<table width="100%" border="1" style="border-collapse:collapse;">
 +
<tr>
 +
<td><b>Name</b></td>
 +
<td><b>Value</b></td>
 +
<td><b>Unit</b></td>
 +
<td><b>Description</b></td>
 +
<td><b>Reference</b></td>
 +
</tr>
 +
<tr>
 +
<td>S<sub>p</sub></td>
 +
<td>0.03</td>
 +
<td>mol.s<sup>-1</sup></td>
 +
<td>Iron pulse</td>
 +
<td><a href="#Ref">[1][2]</a></td>
 +
</tr>
 +
<tr>
 +
<td>v</td>
 +
<td>7*10<sup>-3</sup></td>
 +
<td>m.s<sup>-1</sup></td>
 +
<td>Chyme's flow average speed</td>
 +
<td><a href="#Ref">[2]</a></td>
 +
</tr>
 +
<tr>
 +
<td>L</td>
 +
<td>0.3</td>
 +
<td>m</td>
 +
<td>Duodenum length</td>
 +
<td><a href="#Ref">[3]</a></td>
 +
</tr>
 +
<tr>
 +
<td>α</td>
 +
<td>0.3</td>
 +
<td>s<sup>-1</sup></td>
 +
<td>Duodenum absorption rate</td>
 +
<td><a href="#Par">tuned</a></td>
 +
</tr>
 +
<tr>
 +
<td>σ</td>
 +
<td>0.72</td>
 +
<td>s<sup>-1</sup></td>
 +
<td>Regulation coefficient</td>
 +
<td><a href="#Par">tuned</a></td>
 +
</tr>
 +
</table>
 +
</p>
 +
 
 +
<h2>Sensitivity Analysis</h2>
 +
 
 +
As two parameters cannot be tuned: α and σ, we had to study the stability of the model with respect to the change in these parameters.
 +
 
 +
<h3>Model response in function of α</h3>
 +
 
 +
We start by varying α and keeping σ to its tuned value. This gives the results presented in Figure 4 below.
 +
 
 +
<div align="center">
 +
<a id="Fig4"></a>
 +
<div class="captionedPicture" style="width:100%;">
 +
  <a title="Absorption" href="https://static.igem.org/mediawiki/2013/1/18/Health_sensi_alpha.png">
 +
    <img alt="Absorption" src="https://static.igem.org/mediawiki/2013/1/18/Health_sensi_alpha.png" class="Picture"/>
 +
  </a>
 +
  <div class="caption">
 +
    <b>Figure 4 : </b> Sensitivity analysis for the α parameter, the x axis is in log scale. The curves show the maximal value attained for each simulation.
 +
  </div>
 +
</div>
 +
</div>
 +
 
 +
<p>
 +
The dynamic of the model is not changed α < 1 but, as α gets bigger, the absorbed iron increase greatly, crossing the green (maximal absorption for healthy patient) for α < 10.
 +
</p>
 +
 
 +
<h3>Model response in function of σ</h3>
 +
 
 +
<p>
 +
We do the same simulations with different values for the σ parameter, keeping the α to its tuned value. The result of these simulations is presented in Figure 5.
 +
</p>
 +
 
 +
<div align="center">
 +
<a id="Fig5"></a>
 +
<div class="captionedPicture" style="width:60%;">
 +
  <a title="Absorption" href="https://static.igem.org/mediawiki/2013/1/13/Health_sensi_sigma.png">
 +
    <img alt="Absorption" src="https://static.igem.org/mediawiki/2013/1/13/Health_sensi_sigma.png" class="Picture"/>
 +
  </a>
 +
  <div class="caption">
 +
    <b>Figure 5: </b> Sensitivity analysis for the σ parameter, the x axis is in log scale. The curves show the maximal value attained for each simulation.
 +
  </div>
 +
</div>
 +
</div>
 +
 
 +
<p>
 +
As expected with the equation, the σ parameter shows a sigmoid decreasing shape affecting a lot the iron absorption.
 +
</p>
 +
 
 +
<h3>Model response in function of α and σ</h3>
 +
 
 +
As the model possesses only two free parameter, it is possible to do the joint analysis of the two parameters. This analysis is shown in Figure
 +
 
 +
<div align="center">
 +
<a id="Fig6"></a>
 +
<div class="captionedPicture" style="width:60%;">
 +
  <a title="Absorption" href="https://static.igem.org/mediawiki/2013/2/27/Health_sensi_alpha_sigma.png">
 +
    <img alt="Absorption" src="https://static.igem.org/mediawiki/2013/2/27/Health_sensi_alpha_sigma.png" class="Picture"/>
 +
  </a>
 +
  <div class="caption">
 +
    <b>Figure 6 : </b> Sensitivity analysis for both α and σ parameters. The curves show the maximal value attained for each simulation.
 +
  </div>
 +
</div>
 +
</div>
 +
 
 +
<p>
 +
The dynamics of the model in function of the two parameters is interesting as we can see that the σ value only modify linearly the dynamics. Whereas the α values modify it in an exponential way as it becomes close to zero. The parameter to tune the more carefuly is the α parameter.
</p>
</p>
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<h2>Models and scripts</h2>
<h2>Models and scripts</h2>
<p>
<p>
-
This model was made using the Python language. You can <a href="https://static.igem.org/mediawiki/2013/2/2e/Duodenum.zip"> download the python script here</a>.
+
This model was made using the Python language. You can <a href="https://static.igem.org/mediawiki/2013/d/d8/Healthy.zip"> download the python script here</a>.
</p>
</p>
Line 157: Line 302:
<div id="citation_box">
<div id="citation_box">
<a id="Ref"></a>
<a id="Ref"></a>
-
  <p id="references">References:</p>
+
  <p id="references"><b>References:</b></p>
  <ol>
  <ol>
<li>Physiol Rev 93: 1721–1741, 2013 doi:10.1152/physrev.00008.2013 - Tomas Ganz "SYSTEMIC IRON HOMEOSTASIS"</li>
<li>Physiol Rev 93: 1721–1741, 2013 doi:10.1152/physrev.00008.2013 - Tomas Ganz "SYSTEMIC IRON HOMEOSTASIS"</li>

Latest revision as of 18:40, 14 January 2014

Iron coli project

Disease model

Introduction

In the very beginning of the project, we focused on iron absorption by the duodenum. We first had to model the behaviour of the duodenum regarding iron absorption to determine if a flush treatment strategy was viable.

Observations

We know that 60% of iron is absorbed in the duodenum and 40% in the jejunum. The duodenum is located in the upper intestines, right after the stomach, and is usually 300mm long.
A healthy person absorbs about 10% (1-2mg a day) of the daily iron uptake, while a hemochromatosic patient's absorption varies between 50% and 100% of the daily iron uptake[1].

Absorption
Figure 1 : Overview of the iron regulation system in human body.

Iron absorption is normally regulated by the liver through hepcidin production (depicted in Figure 1). This means that after a certain delay, iron absorption eventually reaches a stationary phase.

Goals

We wanted to build a generic duodenal iron absorption model so that:

  • We can have a realistic base for the Final flush treatment model
  • The model can can be reused in the future for any similar model of absorption.

Assumptions

  • Our bacteria doesn't settle in the duodenum
  • No regulation of the patient's iron absorption
  • Constant iron flow in the duodenum lumen
  • Homogeneous fluid
  • The bacterial quantity is constant
  • The bacterial natural absorption is insignificant compared to the chelation
  • The patient ingests 20mg of iron per day (Guideline Daily Amounts)

Materials and methods

This model simulates the digestion process of one meal from the duodenum's point of view.
The duodenum is considered as a cylinder in which a homogeneous fluid flows. The model is divided into three steps: the filling of duodenum, the steady state flowing step and the emptying.
This model has two variables : the iron dissolved in the duodenum lumen (S) and the absorbed iron (A).
We considered the chyme arrives in the duodenum at a constant rate. S has a linear component Sp which represents the pulses. The also are an emptying component and an absorption component.
We assumed a linear absorption and a negative feedback regulation for A.

Finally:

Name Unit Description
A mg Absorbed Iron
S mg Iron in Duodenum
Sp mol.s-1 Iron pulse
v m.s-1 Chyme's flow
L m Duodenum length
α s-1 Duodenum absorption rate
σ s-1 Regulation coefficient

Parameters tuning :

As the iron absorption process greatly differs from an individual to an other, α and σ cannot be related with anything in the litterature. We thus had to tune those parameters.
First of all, we know that a hemochromatosic patient absorbs at least 50% of the iron he ingests. Thus, we tuned α to fit this information while assessing σ = 0 (Hemochromatosis : no regulation in iron absorbtion).
Then, since we know that a healthy person absorbs 10% of the ingested iron, we were able to tune σ.

Results

These curves represent the total absorbed iron (in red) and the instant iron quantity in the duodenum lumen (blue).
The green line is a landmark: it represents the iron absorption of a healthy person during an average meal.

Absorption
Figure 2 : Ambient and absorbed Iron for a Healthy person
The Figure 2 represents what would normally happen during an average meal. It will be a sample graph for our model.


Absorption
Figure 3 : Ambient and absorbed Iron for a hemochromatosic person.

The Figure 3 was generated with the same equations as the Figure 2, but where σ = 0, which means that there is no regulation of iron absorption.

Parameter values

Name Value Unit Description Reference
Sp 0.03 mol.s-1 Iron pulse [1][2]
v 7*10-3 m.s-1 Chyme's flow average speed [2]
L 0.3 m Duodenum length [3]
α 0.3 s-1 Duodenum absorption rate tuned
σ 0.72 s-1 Regulation coefficient tuned

Sensitivity Analysis

As two parameters cannot be tuned: α and σ, we had to study the stability of the model with respect to the change in these parameters.

Model response in function of α

We start by varying α and keeping σ to its tuned value. This gives the results presented in Figure 4 below.
Absorption
Figure 4 : Sensitivity analysis for the α parameter, the x axis is in log scale. The curves show the maximal value attained for each simulation.

The dynamic of the model is not changed α < 1 but, as α gets bigger, the absorbed iron increase greatly, crossing the green (maximal absorption for healthy patient) for α < 10.

Model response in function of σ

We do the same simulations with different values for the σ parameter, keeping the α to its tuned value. The result of these simulations is presented in Figure 5.

Absorption
Figure 5: Sensitivity analysis for the σ parameter, the x axis is in log scale. The curves show the maximal value attained for each simulation.

As expected with the equation, the σ parameter shows a sigmoid decreasing shape affecting a lot the iron absorption.

Model response in function of α and σ

As the model possesses only two free parameter, it is possible to do the joint analysis of the two parameters. This analysis is shown in Figure
Absorption
Figure 6 : Sensitivity analysis for both α and σ parameters. The curves show the maximal value attained for each simulation.

The dynamics of the model in function of the two parameters is interesting as we can see that the σ value only modify linearly the dynamics. Whereas the α values modify it in an exponential way as it becomes close to zero. The parameter to tune the more carefuly is the α parameter.

Conclusion

This model provides rational results regarding the iron absorption phenomenon. Therefore, we will be able use it as a base for the next simulations.
The next step is to include our bacterial flow in this model, which will result in the Final flush treatment model.

Models and scripts

This model was made using the Python language. You can download the python script here.

References:

  1. Physiol Rev 93: 1721–1741, 2013 doi:10.1152/physrev.00008.2013 - Tomas Ganz "SYSTEMIC IRON HOMEOSTASIS"
  2. Calculated from : Computational Modeling and Simulation of the Human Duodenum - B. Hari, S. Bakalis, P. Fryer - 2012
  3. Wikipedia