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Mamanlian synthetic biology: Single Cell Tumor Microenvironment Profiling under Oncolytic Virotherapy

  • Full or part time
  • Application Deadline
    Sunday, January 12, 2020
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

Dual award PhD in Synthetic and Systems Biology - Manchester and Tsinghua University.

The University of Manchester and China’s Tsinghua University have come together to offer a unique dual degree PhD programme in Synthetic and Systems Biology, with successful applicants spending four life-changing years across Manchester and Beijing. The first-of-its-kind dual award PhD programme brings together two globally-renowned institutions at the forefront of research in this area: the Manchester Institute of Biotechnology (MIB) at The University of Manchester, and the Center for Synthetic and Systematic Biology (CSSB) at Tsinghua University in Beijing, China.

Students will spend two years at Manchester and two years at Tsinghua University, with supervisors in both locations. At the end of the four-year full-time programme, you will receive a dual PhD, one award and two certificates.

Project Description:
Oncolytic virus, which can be programmed to selectively lysis tumor cell and secrete immunomodulators, is a highly versatile platform for cancer treatment and has been reported to trigger systematic immune responses. With the help of synthetic biology, sophisticatedly constructed gene circuits are adopted to control its replication and expression of immune effectors. By encoding and locally releasing cytokines and chemokines , therapeutic efficacy of oncolytic virus against tumors can be greatly enhanced, which helps to overcome immunosuppression in tumor microenvironment with reduced side effect compared to systematic administration of immunomodulators. However, the specific mechanism of how immune system responds to oncolytic virus in tumor microenvironment remains to be examined.
Effective cancer immunotherapy depends on the status of the immune response in the tumor microenvironment, and tumor eradication requires both a high density of effective tumor-infiltrating lymphocytes and immune recognition of tumor-associated antigens. With the development of high-throughput single-cell sequencing technology, cellular level information of immune cell as well as immune repertoire can be simultaneously revealed at large scales. Transcriptome, proteome, sptial heterogeneity features and paired T cell receptor anylysis could help us better understand the synergistic effect around oncolytic virus and immune system. After specific virotherapy, whether tumor-infiltrating lymphocytes could be recruited to immune-deserted areas, whether the suppressed immune functions could be unrestrained and whether tumor-targeting cytotoxic lymphocytes are enriched, can all be well explained by single cell anaylysis. The cancer-targeting specificity of oncolytic virus is also critical for the safety and efficacy of oncolytic virus immunotherapy. Single cell transcriptome heterogeneity profiling of both tumor cells and non-tumor cells illustrates populations that virus can and cannot attack and express in, so synthetic gene circuits could be optimized to further reduce its pathogenicity and raise its specificity.
In this project, several single cell experiments will be performed on immune-competent mouse models. By comparing immune responses produced by different desgins of oncolytic virus, and responses treated with different combinational immunotherapies, possible modifications could be raised to better programe it for the purpose of intensifing immune modulcation against tumors while limiting antiviral and side effects.

Cai Lab at Manchester: http://www.cailab.org
Xie Lab at Tsinghua: http://www.moebioinfo.tsinghua.edu.cn/team/guding/item/473-2016-09-07-15-01-52

Applicants should hold (or be about to obtain) a minimum 2:1 bachelor’s degree (or overseas equivalent), a master’s degree (including an integrated masters degree) or extensive research experience - such as an industry placement - in a relevant discipline. Applicants can be internal or external to The University of Manchester. For applicants whose first language is not English, we require a minimum IELTS score of 6.5/TOEFL 90

programme name: synbiodual

Funding Notes

This is a 4 year fully funded studentship covering tuition fees and stipend (£15,009 in 2019-20 while in Manchester, and a commensurate stipend while at Tsinghua). You will also receive an annual Research Training Support Grant towards project running costs/consumables while in Manchester, and flight allowance for travelling to Tsinghua will be covered.

References

1. Huang Huiya, et al. "Oncolytic adenovirus programmed by synthetic gene circuit for cancer immunotherapy." Nature communications 10.1 (2019): 1-15.
2. Bommareddy, Praveen K., Megha Shettigar, and Howard L. Kaufman. "Integrating oncolytic viruses in combination cancer immunotherapy." Nature Reviews Immunology 18.8 (2018): 498.

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