Difference between revisions of "Team:CSU CHINA/Description"

 
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        <h1 style="text-align:center;margin-bottom:50px">DESCRIPTION</h1>
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<h2 style="text-align:center">Overall Introduction</h2>
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<p style="text-align:justify;margin-right:80px;margin-left:80px;">Based on the high heterogeneity and invasiveness of TNBC, our team has characterized a gene circuit with three modules. Controlled by TNBC-specific promoter 1, module 1 includes a miRNA binding site(BS) and a transcription factor which drives Module3 --- expression of a fusion protein composed of HIF1-αoDDD and yeast cytosine deaminase (yCD) working under hypoxia conditions. Module 2 includes several sponge-like domains effectively down-regulating specific miRNA when promoter 2 is driven. Supposing the miRNA is highly expressed in the normal cells and low in most cancer cells, this circuit could trigger highly selective cytotoxicity of cancer cells. Once optimized, our design could be applied to current treatments, allowing for a more powerful therapeutic effect with a comparatively low risk.</p>
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        <h2 style="text-align:center;margin-top:80px">Status 1(in TNBC cells)</h2>
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<p class="notoi" style="text-align:center;margin-bottom:60px" >High efficiency of P1 + low miRNA expression + hypoxia=kill</p>
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<h2 style="text-align:center;margin-top:80px">Status 2(in TNBC cells)</h2>
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<p class="notoi" style="text-align:center;margin-bottom:60px">High efficiency of P1&P2 + relatively high expression of miRNA + hypoxia=kill</p>
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<p class="notoi" style="text-align:center;margin-bottom:60px">Little expression of GAD nor sponge=not kill</p>
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<p class="notoi" style="text-align:center;margin-bottom:60px">Relative high efficiency of P1 + low efficiency of P2 +high level of miRNA + normoxia=not kill</p>
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        <h1 style="text-align:center;margin-top:100px;margin-bottom:40px">INSPIRATION</h1>
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         <p style="text-align:justify;margin-right:60px;margin-left:60px;">Cancer treatment has always been the hottest issue in society, and a medical documentary called "The World" has recently attracted public attention. Through it, we see disease, death, and people who never give up hope. One episode tells the story of a triple-negative breast cancer patient, whose story is moving but struggle. Chemotherapy once a week and review once a forty-two day is the routine of chemotherapy for a cancer patient. Chemotherapeutic drugs cause vomiting, hair loss, skin darkening, nails, skin decay, and normal cells in the body to collapse which aims to kill the cancer cells that are latent in them.And even if we treat in this way ,it is still ineffective for some cancer cells.</p>
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         <p style="text-align:justify;margin-right:60px;margin-left:60px;">In this documentary, we feel the happiness and sadness when suffering and waiting of a family of triple negative breast cancer patients. Her anti-cancer story has attracted a lot of people including us. After consulting the teachers, we determined that the general direction of the subject was related to the treatment of triple negative breast cancer.</p>
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         <p style="text-align:justify;margin-right:60px;margin-left:60px;">It hurts to see that thousands of women as well as men each year tormented by breast cancer both physically and mentally. Despite success in several clinical trials, triple negative breast cancer(TNBC )still remains a major challenge in fundamental research.  So our goal is to design a genetic gene circuit which is able to trigger cancer specific cytotoxicity in TNBC.</p>
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         <p style="text-align:justify;margin-right:60px;margin-left:60px;">For our project, we consulted Professor Guang Wenyan of the Third Xiangya Hospital. Professor Wen said that in our experiments, it is important to find transcription factors or promoters specifically expressed in the breast so that the system can be specifically expressed in breast cells. If it's not targeted at the breast, it doesn't make sense.Indeed, synthetic biology is not a subject created from scratch, it’s the subtle combination of nature organism and laboratory trials . So ,we utilize the nature marker of TNBC, such as miRNA and cancer specific promoter to guarantee a cancer specific circuit.</p>
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         <p style="text-align:justify;margin-right:60px;margin-left:60px;">As for the safety of gene therapy, Professor Wen said that the main problem lies in the carrier, followed by specificity .The carrier like viral bacterial vectors may be prone to problems. So instead of using viral bacterial vectors, we use transferrin combined with liposomes to directly target cancer cells. In this way, targeting can be very good with transduction efficiency being relatively high thus to reduce the risk.</p>
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         <p style="text-align:justify;margin-right:60px;margin-left:60px;">On the issue of specificity, we introduce Boolean logic——AND gate to initiate our three modules, which generates combinatorial outputs only when all three promoters are mutually active. With mathematical modeling and systematical calculation, this genetic circuit with efficiency and specificity could be promising in future treatment.</p>
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              Introduction
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          Triple-negative breast cancer (TNBC), is a special subtype of breast cancer with a poor overall prognosis. Among all breast cancer patients in China, TNBC accounts for about 10-20% of breast cancer. It is more likely to occur in relatively young women, our of its highly invasive and easy to prone to visceral metastasis. The poor prognosis of TNBC is the difficulty in clinical treatment. So gene targeting TNBC is one of the best treatments of choice in the future years.
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          In this way, we choose to treat TNBC with synthetic biology by the light of nature. In order to treat the TNBC, we design three modules to solve the main two difficulties: specificity and heterogeneity. Our inspiration came from that ‘Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer Immunotherapy’. They comprised de novo synthetic cancer-specific promoters and, to enhance specificity, an RNA-based AND gate that generates combinatorial immunomodulatory outputs only when both promoters are mutually active (Figure1). So we are lighted to design the control gene circuit including specific promoter, sponge structure and miR-BS, and finally to trigger the death of the TNBC cells.
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          In short, the three modules each performs their own functions and integrated tightly: Module1 is used to identify the normal cell and cancer cell;  Module2 enhance the specificity of the identical system and also capture the heterogeneous cancer cells. Module3 is a killer to trigger death of the cancer cells which we proposed to design a HIF1αODDD-yCD fusion protein to convert 5-FC to toxic 5-FU [2]. For more information, you guys can go to the following pages!
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      <div class="largeword">Description</div>
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                  <span style="font-size: 2.2rem;color: rgb(30, 36, 39);"> Breast cancer </span> known as one of the most infamous cancer, is the leading cause of death of cancer among women worldwide.
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              Breast cancer can be had by male, due to the fact that breast existing in both male and female. The breast is mainly composed of fatty tissue. More glandular tissue making up 12 to 20 mammary lobules in which milk is produced can usually be found in women’s breast than men’s.
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              Breast epithelial cells are not regulated by the body and are constantly multiplying due to variety of reasons such as genetic mutations and epigenetic changes, which will gradually compress the surrounding tissue and form a lump. This is the beginning of cancer.
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                Breast cancer is also a highly heterogeneous cancer. Usually it is classified into four types based on the combination of ER, PR and HER2 receptor molecules on the cell surface.
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            Clinically, several drugs such as tamoxifen and raloxifene have been developed for ER based on the fact that it is a characteristic of Luminal A and B to inhibit the uptake of estrogen by cancer cells, thereby inhibiting the proliferation of cancer cells. Similarly, monoclonal antibody Trastuzumab was used against HER2+ positive breast cancer cells by block the HER2+ receptor and inhibiting EGF absorption, thereby preventing further proliferation of cancer cells.
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            Clinically, several drugs such as tamoxifen and raloxifene have been developed for ER based on the fact that it is a characteristic of Luminal A and B to inhibit the uptake of estrogen by cancer cells, thereby inhibiting the proliferation of cancer cells. Similarly, monoclonal antibody Trastuzumab was used against HER2+ positive breast cancer cells by block the HER2+ receptor and inhibiting EGF absorption, thereby preventing further proliferation of cancer cells.
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          However, marker molecules such as ER, PR and HER2 are not present in some cancer cells which is called triple-negative breast cancer (TNBC), so there is no effective targeted therapy for these kinds of cancers. This type of cancer is aggressive, fatal and difficult to treat.
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        <h3>References:</h3>
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        <p>[1] Lior Nissim, Ming-Ru Wu, Erez Pery, Adina Binder-Nissim, Hiroshi I. Suzuki, Doron Stupp, Claudia Wehrspaun, Yuval Tabach, Phillip A. Sharp, and Timothy K. Lu, Cell, (2017),Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer Immunotherapy.</p>
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        <p>[2] Tiana D. Warren,† Krishna Patel,† James R. Eshleman,‡,§ and Marc Ostermeier, ACS Synth. Biol, Protein-Programmed Accumulation of Yeast Cytosine Deaminase in Cancer Cells in Response to Mock-Hypoxia.</p>
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Latest revision as of 20:12, 5 December 2019

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CSU_CHINA_TEAM
Introduction
Triple-negative breast cancer (TNBC), is a special subtype of breast cancer with a poor overall prognosis. Among all breast cancer patients in China, TNBC accounts for about 10-20% of breast cancer. It is more likely to occur in relatively young women, our of its highly invasive and easy to prone to visceral metastasis. The poor prognosis of TNBC is the difficulty in clinical treatment. So gene targeting TNBC is one of the best treatments of choice in the future years.
In this way, we choose to treat TNBC with synthetic biology by the light of nature. In order to treat the TNBC, we design three modules to solve the main two difficulties: specificity and heterogeneity. Our inspiration came from that ‘Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer Immunotherapy’. They comprised de novo synthetic cancer-specific promoters and, to enhance specificity, an RNA-based AND gate that generates combinatorial immunomodulatory outputs only when both promoters are mutually active (Figure1). So we are lighted to design the control gene circuit including specific promoter, sponge structure and miR-BS, and finally to trigger the death of the TNBC cells.
In short, the three modules each performs their own functions and integrated tightly: Module1 is used to identify the normal cell and cancer cell; Module2 enhance the specificity of the identical system and also capture the heterogeneous cancer cells. Module3 is a killer to trigger death of the cancer cells which we proposed to design a HIF1αODDD-yCD fusion protein to convert 5-FC to toxic 5-FU [2]. For more information, you guys can go to the following pages!
Description
Breast cancer known as one of the most infamous cancer, is the leading cause of death of cancer among women worldwide.
Breast cancer can be had by male, due to the fact that breast existing in both male and female. The breast is mainly composed of fatty tissue. More glandular tissue making up 12 to 20 mammary lobules in which milk is produced can usually be found in women’s breast than men’s.
Breast epithelial cells are not regulated by the body and are constantly multiplying due to variety of reasons such as genetic mutations and epigenetic changes, which will gradually compress the surrounding tissue and form a lump. This is the beginning of cancer.
Breast cancer is also a highly heterogeneous cancer. Usually it is classified into four types based on the combination of ER, PR and HER2 receptor molecules on the cell surface.
Clinically, several drugs such as tamoxifen and raloxifene have been developed for ER based on the fact that it is a characteristic of Luminal A and B to inhibit the uptake of estrogen by cancer cells, thereby inhibiting the proliferation of cancer cells. Similarly, monoclonal antibody Trastuzumab was used against HER2+ positive breast cancer cells by block the HER2+ receptor and inhibiting EGF absorption, thereby preventing further proliferation of cancer cells.
Clinically, several drugs such as tamoxifen and raloxifene have been developed for ER based on the fact that it is a characteristic of Luminal A and B to inhibit the uptake of estrogen by cancer cells, thereby inhibiting the proliferation of cancer cells. Similarly, monoclonal antibody Trastuzumab was used against HER2+ positive breast cancer cells by block the HER2+ receptor and inhibiting EGF absorption, thereby preventing further proliferation of cancer cells.
However, marker molecules such as ER, PR and HER2 are not present in some cancer cells which is called triple-negative breast cancer (TNBC), so there is no effective targeted therapy for these kinds of cancers. This type of cancer is aggressive, fatal and difficult to treat.

References:

[1] Lior Nissim, Ming-Ru Wu, Erez Pery, Adina Binder-Nissim, Hiroshi I. Suzuki, Doron Stupp, Claudia Wehrspaun, Yuval Tabach, Phillip A. Sharp, and Timothy K. Lu, Cell, (2017),Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer Immunotherapy.

[2] Tiana D. Warren,† Krishna Patel,† James R. Eshleman,‡,§ and Marc Ostermeier, ACS Synth. Biol, Protein-Programmed Accumulation of Yeast Cytosine Deaminase in Cancer Cells in Response to Mock-Hypoxia.



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