Investigating the effects of surfactant proteins in ovarian cancer progression
Ovarian cancer is one of the most common types of cancer in in women; every year 7,000 women are diagnosed in UK. It is the second most common occurring in the reproductive tract and the fifth overall. It is associated with very high mortality; after 5 years typically less than one third of patients diagnosed are still surviving. The cure rate for women with ovarian cancer has not significantly changed over the past 10 years. Surfactant proteins are important for clearing pathogens, maintaining pulmonary homeostasis and survival. These proteins have been localised in various parts of the human reproductive tract, including the ovaries. Surfactant protein D (SP-D) has recently been implicated in cancer and has been reported to have an inhibitory role. Tumour cells can be affected by the inflammatory environment and that can have an effect on tumour proliferation and metastasis, thus making surfactant proteins’ role even more important.
We hypothesised that SP-D has a potential inhibitory role in ovarian cancer progression since it is expressed in various parts in the reproductive tract. The main objectives are:
1. Identify the effects of intrauterine tissue secreted proteins on cancer cell proliferation. For this, conditioned media from myometrial and endometrial cells treated with SP-D will be used to treat 3 distinct human ovarian cancer cell lines.
2. Study the effects of SP-D on gene expression of surfactant proteins and mTOR pathway components.
3. Elucidate the effects of SP-D on cell proliferation as well as apoptosis or involvement in any other cytotoxic or cytostatic events.
For this project we will employ a wide repertoire of molecular, cellular and biochemical techniques. All techniques are well established, so no caveats are anticipated.
How to apply
If you are interested in applying for the above PhD topic please follow the steps below:
- Contact the supervisor by email or phone to discuss your interest and find out if you woold be suitable. Supervisor details can be found on this topic page. The supervisor will guide you in developing the topic-specific research proposal, which will form part of your application.
- Click on the 'Apply here' button on this page and you will be taken to the relevant PhD course page, where you can apply using an online application.
- Complete the online application indicating your selected supervisor and include the research proposal for the topic you have selected.
This is a self funded topic
Brunel offers a number of funding options to research students that help cover the cost of their tuition fees, contribute to living expenses or both. See more information here: https://www.brunel.ac.uk/research/Research-degrees/Research-degree-funding. The UK Government is also offering Doctoral Student Loans for eligible students, and there is some funding available through the Research Councils. Many of our international students benefit from funding provided by their governments or employers. Brunel alumni enjoy tuition fee discounts of 15%.
Meet the Supervisor(s)
- I studied biology in the school, did B.Sc. in Zoology and M.Sc. in Cell Biology, and went on to carry out PhD research in molecular biology from Delhi. After a short stint at Salk Institute, San Diego as a NASA fellow, I joined in 1996 Department of Biochemistry, Oxford, first as a Wellcome Trust Overseas Fellow, and then as a Research Associate within Medical Research Council Immunochemistry Unit. At Oxford, I became interested in pattern recognizing innate immune molecules such as complement protein C1q and pulmonary surfactant proteins SP-A and SP-D. The identification of a major role of SP-D in controlling pulmonary inflammation and infection by our group took me further into host-pathogen interaction. I became involved in a range of projects that culminated in demonstrating that recombinant SP-D can have therapeutic potential again pulmonary hypersensitivity and invasive infection. Since then, I have been concentrating on clinical aspects of the above mentioned proteins that have ramifications as far as asthma, infection, autoimmunity, transplantation and a number of neonatal conditions. My current interest lies in role of innate immunity in host defence using a model fungal pathogen, Aspergillus fumigatus. This pathogen causes allergic bronchopulmonary aspergillosis (ABPA) in immunocompetent individuals, while being capable of causing fatal invasive aspegillosis in immunocompromised subjects. Human SP-D is a pulmonary surfactant-associated innate immune molecule. Our studies have established its potent anti-microbial and anti-inflammatory properties in vitro, in vivo and ex vivo. Using a murine model of severe lung infection (invasive pulmonary aspergillosis, IPA) caused by a fungal pathogen, Aspergillus fumigatus (Afu), we found that treatment with rhSP-D can rescue mice from certain death. All untreated IPA mice died within 5-7 days, the rhSP-D treated group showed >90% survival (without any side effects). The SP-D mediated protective mechanisms include agglutination of pathogen, fungistasis, enhanced killing by phagocytes and predominant Th1 response. Increased susceptibility of SP-D gene deficient mice to IPA supports our view. Patients, who are immunocompromised or immunodeficient due to chemotherapy, cancer, transplantation or AIDS are high risk IPA groups. Using animal models of asthma caused by Afu and dust mite, we have shown that rhSP-D has a long term therapeutic value in dampening asthmatic symptoms in mice. The therapeutic mechanisms include inhibition of allergen-IgE binding and histamine release by sensitized mast cells, dramatic downregulation of specific IgG and IgE antibodies and pulmonary and peripheral eosinophilia, a shift from pathogenic Th2 to a protective Th1 cytokine response, inhibition of mechanisms that cause airway remodelling, and apoptosis induction in sensitised eosinophils. This is consistent with inherent hypereosinophilia and Th2 predominance, and hence increased susceptibility of SP-D gene deficient mice, to allergic hypersensitivity. Thus, another important milestone in sight is to evaluate therapeutuc efficacies of a recombinant form of human SP-D in patients suffering from asthma and lung infection. I aim to further understand how SP-D modulates immune responses, and how it maintains persistence of its therapeautic effect. Using animal models of ABPA and IPA in wild type and SP-D knock out mice, we will try to understand how SP-D modulates eosinophils, dendritic cells (DC), and helper T cell polarisation to protective Th1 response that are so central to therapeutic mechanisms. In addition, I remain interested in structural and functional aspects of the globular head region of human C1q, the first subcomponent of the classical complement pathway. The potential application of the recombinant forms of C1q globular head domains in dampening complement activation in a range of inflammatory conditions including neurodegenerative diseseaes is also being explored on my laboratory. A number of above mentioned studies have led to setting up of clinical trials, which remain at the core of my translational research.Qualifications: -
- PhD (1995): Department of Zoology, University of Delhi and CSIR Institute of Genomics and Integrative Biology, Delhi, Indi Thesis: Chemical gene synthesis and expression of Human Epidermal Growth Factor in Escherichia coli.
- Dr Manos Karteris graduated with a BSc (Hons) in Medical Biochemistry from the University of Surrey in 1995. He then was awarded an MSc with Distinction in Medical Genetics with Immunology from Brunel University London in 1996 and completed his PhD in Molecular Endocrinology from the University of Warwick in 2000. He then undertook post-doctoral appointments at the University of Warwick, including a prestigious VIP Research Fellowship from the Wellcome Trust. He was appointed as Lecturer in Endocrinology at the University of Warwick from 2005-2006 and then he transferred to Brunel University London as a Lecturer in Biomedical Sciences in June 2006. In October 2017 Dr Karteris became a Senior Lecturer in the Division of Biomedical Sciences. He is also the head of the Cancer Biomarkers and Cellular Endocrinology Lab (CBCEL). For more information please visit the lab webpage: www.cbcel.org
BSc Medical Biochemistry, University of Surrey
MSc Medical Genetics with Immunology, Brunel University
PhD Molecular Endocrinology, University of Warwick
PGCert HE & PGCERT IP Law, Brunel University
Related Research Group(s)
Organ-on-a-Chip - The group’s main research focus is on women’s health and developing four main organ-on-a-chip (OOC) models: the breast, vagina, ovary, and placenta.