<h1> <FONT FACE="Arial,Helvetica,sans-serif"> JDRF Funded Research</h1> <table width = "600" > <tr> <td><FONT SIZE="-1" FACE="Arial,Helvetica,sans-serif"><B>JDRF-Funded Research: Lay Abstract </b></font> </td> </tr> </table> <br> <table cellpadding="0" border="0" width="800" cellspacing="2"> <tr> <td width = "60%" bgcolor = "4978AC" height = "20" align="left"> <font color="FFFFFF" face="Arial,Helvetica,sans-serif" size="2"> <strong>PI Name:</strong> Chandrabali Bhattacharya <br> <strong>Institution Name:</strong> Massachusetts Institute of Technology<br> <!--strong>Lab Website:</strong> http://web.mit.edu/<br>--><br> <strong>Project duration:</strong> 01-February-2018 to 31-July-2021<br> <strong>Mechanism:</strong> Postdoctoral Fellowship<br> <strong>Project grant award: </strong>$202,038.19*<br> * Total Grant award amount may vary depending on budget adjustments and it is contingent upon research progress and availability of JDRF research funds. <br><br> </font> </td> <td width = "40%" bgcolor = "4978AC" height = "20" align="left"><font color="FFFFFF" face="Arial,Helvetica,sans-serif" size="2"> <strong>Grant Key:</strong> 3-PDF-2018-576-A-N<br> <!--strong>Therapeutic Area:</strong> <br>--> <strong>Grant status:</strong> Active Grant<br></font> </td> </tr> </table> <table cellpadding="0" border="0" width="800" cellspacing="2"> <tr> <td width="100%" bgcolor = "6699CC" height = "20" align="left"><FONT FACE="Arial,Helvetica,sans-serif" SIZE="2" COLOR="FFFFFF"> <strong>Project Title</strong></font> </td> </tr> <tr> <td width = "100%" bgcolor = "EBEBEB" align="justify"><FONT FACE="Arial,Helvetica,sans-serif" SIZE="2"> Novel glucose-responsive tripeptides for smart insulin</font> </td> </tr> </table> <table cellpadding="0" border="0" width="800" cellspacing="2"> <tr> <td width="100%" bgcolor = "6699CC" height = "20" align="left"><FONT FACE="Arial,Helvetica,sans-serif" SIZE="2" COLOR="FFFFFF"> <strong>Objective</strong> </font></td> </tr> <tr> <td width = "100%" bgcolor = "EBEBEB" align="justify"><FONT FACE="Arial,Helvetica,sans-serif" SIZE="2"> Development of “fully synthetic pancreas” in which chemical sensors will quickly respond to elevated blood glucose levels by releasing the appropriate amount of insulin under physiological conditions has emerged as the most promising therapy for control of Type 1 diabetes. Here, we propose a rational design for the development of next generation glucose sensors that could be readily conjugated to insulin and is expected to provide strong and selective glucose binding materials. We will first synthesize and evaluate a library of oligomers modified with glucose-responsive groups. We will then prepare insulin conjugates for those with sensitivity and selectivity toward glucose binding, and finally, we will test them in in mouse model.</font> </td> </tr> </table> <table cellpadding="0" border="0" width="800" cellspacing="2"> <tr> <td width="100%" bgcolor = "6699CC" height = "20" align="left"><FONT FACE="Arial,Helvetica,sans-serif" SIZE="2" COLOR="FFFFFF"> <strong>Background/Rationale</strong> </font></td> </tr> <tr> <td width = "100%" bgcolor = "EBEBEB" align="justify"><FONT FACE="Arial,Helvetica,sans-serif" SIZE="2"> In Type 1 diabetes, the insulin producing pancreatic beta-cells are destroyed by the immune system resulting in absolute insulin deficiency. As insulin maintains the blood glucose levels, this condition results in high blood glucose levels. There is no known cure for diabetes and maintaining the glucose level is critical as proven to be life threatening. Self-administration of insulin injections through skin several times daily combined with close glucose monitoring is an important component in managing diabetes. The traditional insulin therapy is expensive, painful and inconvenient for patients. Over the past few years, our lab is working towards different diabetes therapies including islet cell therapy. This has further inspired research efforts toward the development of “fully synthetic pancreas” in which chemical sensors will quickly respond to elevated blood glucose levels by releasing the appropriate amount of insulin under physiological conditions. Herein, we will explore the next generation glucose-responsive chemosensors having glucose-responsive functional groups for selective glucose binding. The glucose-responsive molecules will be identified and conjugated to insulin will then be tested in mouse model. </font> </td> </tr> </table> <table cellpadding="0" border="0" width="800" cellspacing="2"> <tr> <td width="100%" bgcolor = "6699CC" height = "20" align="left"><FONT FACE="Arial,Helvetica,sans-serif" SIZE="2" COLOR="FFFFFF"> <strong>Description of Project</strong> </font></td> </tr> <tr> <td width = "100%" bgcolor = "EBEBEB" align="justify"><FONT FACE="Arial,Helvetica,sans-serif" SIZE="2"> Type 1 diabetes (T1D), also known as juvenile diabetes, is a growing health crisis all over the world with the total annual global costs amounting to US$500 billion including the treatment related to its complications. The insulin producing pancreatic beta-cells are destroyed by the immune system in T1D resulting in absolute insulin deficiency and high blood glucose levels. There is no known cure for diabetes and control of the glucose level is critical as proven to be life threatening. Self-administration of insulin injections, which is critical in maintaining a healthy normal blood glucose level, is an important component in managing diabetes. As the traditional insulin therapy is expensive, painful and inconvenient for patients, this has inspired research efforts toward the development of “fully synthetic pancreas” in which chemical sensors will quickly respond to elevated blood glucose levels by releasing the appropriate amount of insulin under physiological conditions. In this proposal, we will explore the next generation glucose-responsive chemosensors with physiologically relevant glucose-responsiveness. This will lead to developing for the first time an advanced glucose-responsive insulin conjugates that are sensitive to physiological glucose levels and increase the duration of insulin independence. This will revolutionize insulin delivery therapy and will make the treatment less painful, safer and patient friendly.</font> </td> </tr> </table> <table cellpadding="0" border="0" width="800" cellspacing="2"> <tr> <td width="100%" bgcolor = "6699CC" height = "20" align="left"><FONT FACE="Arial,Helvetica,sans-serif" SIZE="2" COLOR="FFFFFF"> <strong>Anticipated Outcome</strong> </font></td> </tr> <tr> <td width = "100%" bgcolor = "EBEBEB" align="justify"> <FONT FACE="Arial,Helvetica,sans-serif" SIZE="2"> This proposal will develop a novel chemical sensor that will sense changes in glucose level inside the body. Precisely, this chemical sensor will quickly respond to elevated blood glucose levels by delivering a required amount of insulin and terminate after the normal blood glucose level is achieved. Hence, in this proposal we will rationally design the synthesis, evaluate the glucose binding and test the efficacy of these selective glucose binding modules conjugated to insulin in mouse model. This will lead to developing for the first time an advanced glucose-responsive insulin conjugates with physiologically relevant glucose-responsiveness and increase the duration of insulin independence, forming the basis for non-human primates testing and eventually clinical trials. </font> </td> </tr> </table> <table cellpadding="0" border="0" width="800" cellspacing="2"> <tr> <td width="100%" bgcolor = "6699CC" height = "20" align="left"><FONT FACE="Arial,Helvetica,sans-serif" SIZE="2" COLOR="FFFFFF"> <strong>Relevance to Type I Diabetes </strong> </font></td> </tr> <tr> <td width = "100%" bgcolor = "EBEBEB" align="justify"><FONT FACE="Arial,Helvetica,sans-serif" SIZE="2"> As there is no known cure for diabetes, maintaining the glucose level is crucial in the long-term maintenance of diabetes. Development of synthetic glucose binding molecules that can mimic the function of a healthy pancreas toward the release of insulin has emerged as a promising strategy for long-term control of Type 1 diabetes. This proposal is inspired from the intention of identifying a novel chemical sensor that could be readily attached to insulin and sense changes in glucose level inside the body. If successful, this development will revolutionize insulin delivery therapy and will make the treatment less painful, safer and patient friendly. </font> </td> </tr> </table>