Team:UC Davis/Project1

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<div style="text-align: center;"><b style="color: rgb(255, 255, 153);"><span
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style="font-size: 13.5pt; font-family: &quot;Times New Roman&quot;,&quot;serif&quot;;"><big><big><big><big><a
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style="border: 0px solid ; width: 83px; height: 36px;"></a> </big></big></big></big></span></b><a
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href="https://2009.igem.org/Team:UC_Davis/About_Us1"><b
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style="font-size: 13.5pt; font-family: &quot;Times New Roman&quot;,&quot;serif&quot;;"><big><big><big><big><img
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style="font-size: 13.5pt; font-family: &quot;Times New Roman&quot;,&quot;serif&quot;;"><big><big><big><big><a
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href="file:///C:/Davis/iGEM09/igem2009_site/UCDAVIS_Project1.html"><img
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style="font-size: 13.5pt; font-family: &quot;Times New Roman&quot;,&quot;serif&quot;;"><big><big><big><big><a
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href="file:///C:/Davis/iGEM09/igem2009_site/UCDAVIS_Notebook1.html"><img
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href="file:///C:/Davis/iGEM09/igem2009_site/UCDAVIS_Parts1.html"><img
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alt="" src="https://static.igem.org/mediawiki/2009/a/a6/UCDAVIS_PIC6.png"
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style="border: 0px solid ; width: 78px; height: 37px;"></a>&nbsp;<a
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href="file:///C:/Davis/iGEM09/igem2009_site/UCDAVIS_Contacts.html"><img
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alt="" src="https://static.igem.org/mediawiki/2009/1/1d/UCDAVIS_PIC7.png"
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style="border: 0px solid ; width: 83px; height: 37px;"></a></big></big></big></big></span></b><b
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style="color: rgb(0, 0, 0);"><span
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style="font-size: 13.5pt; font-family: &quot;Times New Roman&quot;,&quot;serif&quot;;"><big><big><big><big><small></small></big></big></big></big></span><br>
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</b>
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<hr style="width: 100%; height: 2px;">
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<div style="text-align: center;"><big><big><span
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style="font-weight: bold;">&nbsp; </span></big><big><span
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style="font-weight: bold;">Porject:</span></big><br>
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<a href="#What_is_Celiac_Disease">What is Celiac Disease</a>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
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<a href="#current_treatment">Current Treatment&nbsp;</a>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
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<a href="#our_approach">Our Approach</a><br>
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<span style="font-weight: bold;"><big></big></span></big>
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<ul>
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<li>
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<h1 style="text-align: left; text-decoration: underline;"><a
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name="What_is_Celiac_Disease"></a><small><span class="mw-headline">What
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is Celiac Disease?</span></small></h1>
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</li>
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</ul>
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<h2 style="text-align: left;"><small> <span class="mw-headline">Description</span></small></h2>
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<div style="text-align: left;"></div>
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<p style="text-align: left;">Celiac disease is a form of autoimmune
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disorder that occurs inside
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the small intestines of about one out of every 133 Americans. Affected
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individuals cannot properly digest gliadin (a component of gluten),
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leading to immune responses that may include pain and/or vomiting.
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</p>
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<div style="text-align: left; font-weight: bold;"><big><span
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class="mw-headline">What happens in the normal small intestines?</span></big></div>
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<div style="text-align: left;"></div>
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<p style="text-align: left;">The small intestines are lined with
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numerous protrusions called
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"microvilli", which constitute the brush border membrane. In normal
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small intestines, small peptides and molecules like water diffuse
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through the brush border membrane and into the bloodstream. Larger
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molecules such as gliadin are also allowed to diffuse through, but only
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after they have been converted through a transcellular route.
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</p>
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<h2 style="text-align: left;"><small><span class="mw-headline">What
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happens in celiac disease small intestines?</span></small></h2>
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<div style="text-align: left;"></div>
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<p style="text-align: left;">The brush border membrane in the small
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intestines of people
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suffering from celiac disease allows large molecules such as gliadin to
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go directly into the blood stream without routing them through the
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transcellular path. Once gliadin passes through, antigen-presenting
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cells recognize gliadin as a foreign object and attack. This immune
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response causes pain and other adverse side-effects.
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</p>
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<p style="text-align: left;">Over time, these side-effects may also
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damage intestinal villi,
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which are important for absorbing nutrients. Lack of nutrients can lead
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to other illnesses such as autoimmune thyroid disease, autoimmune liver
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disease, and rheumatoid arthritis (<i>diseases in which body immune
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system attacks healthy cells/tissues</i>) (14).<br>
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</p>
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<hr style="width: 100%; height: 2px;">
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<ul style="text-align: left;">
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<li><small><span class="mw-headline"><a name="current_treatment"></a><big><big
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style="text-decoration: underline;"><big><span
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style="font-weight: bold;">Current Treatments:</span></big></big></big></span></small></li>
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</ul>
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<div style="text-align: left;"></div>
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<p style="text-align: left;">Currently, there is no cure for this
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genetic condition. Prevention
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of the symptoms associated with celiac disease is accomplished through
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adopting a gluten-free diet (14, 12, 11). However, gluten is present in
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most everyday diets, making it difficult to have a gluten-free diet.
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</p>
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<p style="text-align: left;">"Oral supplementation with prolyl
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oligopeptidases has therefore
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been proposed as a potential therapeutic approach."(8) However, enzymes
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studied earlier were not able to degrade gluten inside stomach before
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it reaches small intestine because they were "irreversibly inactivated
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by pepsin and acidic pH, both present in the stomach."(8)
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</p>
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<p style="text-align: left;">Over the past years, researchers
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discovered an enzyme from the bacterium <i>Aspergillus niger</i>.
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This recently identified prolyl endoprotease was observed to "work
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optimally at 4-5 pH and [remain] stable at 2 pH".(8) It is possible
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that this enzyme may provide an alternative treatment for celiac
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disease. (8) Studies have shown that prolyl endoprotease is able to
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"degrade gluten <i>in vitro</i> and under conditions similar to the
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ones present in the gastrointestinal tract." (8) However, due to
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licensing restrictions we have opted not to work with this protein.
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</p>
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<p style="text-align: left;">In 2007, a study suggested an alternative
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approach by combining
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a glutamine-specific endoprotease (EP-B2 from barley) and a prolyl
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endopeptidase (SC PEP from <i>Sphingomonas capsulata</i>); with
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gastric activity and complementary substrate specificity there is a
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possibility of increasing the safe threshold of ingested gluten (12).
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An advantage of this “combination product is that both enzymes are
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active and stable in stomach and can therefore be administered as
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lyophilized powders or simple capsules or tablets” (12).
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</p>
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<p style="text-align: left;"><i>Note: This study was first “evaluated
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via in vitro digestion
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of whole-wheat bread and then confirmed by in vivo studies in rats
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(12), unlike other earlier studies which were performed on synthetic
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gluten oligopeptides, recombinant gliadin proteins, or uncooked gluten”
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(12).<br>
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</i></p>
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<hr style="width: 100%; height: 2px;"></div>
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<h1 style="text-align: left;"><small><span class="mw-headline"></span></small></h1>
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<ul style="text-decoration: underline; text-align: left;">
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<li>
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<h1><small><span class="mw-headline"><a name="our_approach"></a>Our
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Approach</span></small></h1>
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</li>
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</ul>
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<div style="text-align: left;"></div>
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<p style="text-align: left;">&nbsp;&nbsp;&nbsp; We are going to break
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down gluten inside the stomach, because
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gliadin does not prompt an immune system response until absorption in
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the small intestines. Another worry is our delivery system taking
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residence somewhere outside the stomach, so we designed a pH inducible
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apoptosis system. This is achieved through sensing the change of pH
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from the stomach to the small intestine, a difference of about four to
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five.<br>
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Unlike other suggested treatments requiring the consumption of capsules
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or tablets, our method of using <i>Escherichia coli</i> is more cost-
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and time-efficient.<br>
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</p>
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<hr style="width: 100%; height: 2px;">
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<p style="text-align: left; font-weight: bold;"><span
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class="mw-headline">Induced Secretion:</span></p>
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<div style="text-align: left;"></div>
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<ul style="text-align: left;">
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<li>Gene sequence for secretion system
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</li>
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<li>Adding Secretion
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</li>
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<li>Assay for measuring protein localization and activity
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</li>
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</ul>
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<div style="text-align: left;"><span class="editsection"></span><span
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style="font-weight: bold;" class="mw-headline">Sensing pH and Inducing
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Cell Death:</span></div>
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<div style="text-align: left;"></div>
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<ul style="text-align: left;">
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<li>Finding an appropriate biological pH sensor
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</li>
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<li>Wiring the pH sensor into our system
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</li>
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<li>Assay for measuring the behavior of the pH sensor
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</li>
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</ul>
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Latest revision as of 21:40, 25 September 2009

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