Positions available in the Hapgood lab
Applicants are invited to apply to join the Hapgood lab for MSc, PhD or Post Doc positions in 2015. A choice of projects is available. Research projects include investigating molecular mechanisms of gene regulation and cell signalling by steroid receptors, within the context of women's health, HIV-1 transmission/prevention, contraception, as well as cross talk with other signalling pathways. Some grant holder -linked bursaries are available and secure for 3 years. Applicants should send a CV, academic record and names and contact detail of three referees, to Prof Janet Hapgood at Janet.Hapgood@uct.ac.za. A strong background in Biochemistry and/or Chemistry and/or Genetics would be an advantage, as well as experience in molecular biology/biochemistry methods, mammalian tissue culture, signalling, gene regulation, receptors, HIV and/or immunology, as appropriate. Interested applicants would be advised to also apply in 2014 to other granting agencies for bursaries, to enable top ups. Since deadlines for these are imminent, interested candidates should email Prof Hapgood as soon as possible.
Research in the Hapgood Lab in the Department of Molecular and Cell Biology is focussed on how steroids change the biology inside cells and physiological function via their steroid receptors. In particular, they focus on the glucocorticoid receptor (GR), which is the receptor for cortisol, the natural stress hormone in humans. This receptor is also responsible for regulating all aspects of immune function in humans, as well as modulating other functions such as metabolism and reproduction. The GR is a ligand-activated transcription factor that regulates the increased or decreased expression of a number of important genes in the immune system. While the GR is activated by cortisol, the Hapgood lab have shown that other drugs and synthetic hormones, like some progestin contraceptives, are capable of binding to and activating the GR, potentially having negative effects on immune function and susceptibility to infectious diseases.
The role of the GR in modulating immune function and HIV infection:
A major research project in the Hapgood laboratory flowing from the above is investigating cross talk between synthetic hormones used as contraceptives, targeted to the progesterone receptor, and the GR, and how this may cause side-effects on immune function. This project received a major boost in November 2012 by the award to Professor Janet Hapgood of a US$100,000 Grand Challenges Explorations (GCE) grant, an initiative funded by the Bill & Melinda Gates Foundation, on "Determination of differential effects of progestins on HIV-1 infectivity: towards choice of progestin for contraception in high-risk developing countries."
HIV-1 prevalence in young women of childbearing age is very high in sub-Saharan Africa. Pregnancy poses a significant health risk to mothers and babies due to mother-to-child HIV-1 transmission, high infant and maternal mortality, as well as enormous socio-economic challenges. The choice of contraceptive for young women is a particularly important decision. This choice is complicated by controversial clinical findings that some contraceptives significantly increase susceptibility to HIV-1 infection. Thus a crucial health policy issue is to find the best possible method of contraception that most effectively balances risks with health benefits in these regions. Contraceptives can be administered in many different forms, including as injectable compounds, orally, as patches on the skin and in the form of long-acting intra-uterine devices. The actual hormones used, which include synthetic derivatives of the natural hormone progesterone, called progestins, also vary widely in different types of contraceptives. The research proposed by Prof. Janet Hapgood aims to provide insight as to which is the safest progesterone derivative for contraceptive use by women in high risk areas for HIV-1 infection.
Progestins are synthetic hormones designed to act like the natural hormone progesterone, which acts via the progesterone receptor. One of the progestins, medroxyprogesterone acetate (MPA), binds to the GR with relatively high affinity, unlike another progestin norethisterone enanthate (NET). Both MPA and NET are commonly used injectable hormonal contraceptives in South Africa. Two recent publications from the Hapgood laboratory show that MPA, unlike NET and progesterone, repress the immune system in human cervical epithelial cells and human peripheral blood mononuclear cells (PBMCs) (Govender et al., 2014, PLoS One, (Hapgood et al., 2014, Am J Reprod Immunol). Cervical epithelial cells in the female reproductive tract represent the first line of defence in women for heterosexual HIV-1 transmission, while PBMCs are important in fighting systemic infection and contain the T-cells which are target cells for HIV-1. Importantly, these papers identify the mechanism as being via the GR. Further recent papers show that MPA and NET are unlikely to exert such side effects via other steroid receptors such as the mineralocorticoid receptor (MR), but may also exert side effects via the androgen receptor (AR) (Africander et al 2013, Africander et al., 2014). Collectively this work provides fundamental basis for understanding and improved drug/therapeutic interventions for contraception. Importantly, a key recent paper from the Hapgood laboratory provides evidence for the first time that MPA, unlike NET or progesterone, may aid the HIV-1 virus by potentiating death of T-cells in human PBMCs, acting via the GR (Tomasicchio et al., 2013). These findings and their implications for progestin therapy and HIV-1 pathogenesis have been discussed in several recent invited reviews by Prof Hapgood (Stanczyk et al., 2013; Hapgood, 2013, (Endocrinology); Hapgood et al., 2014). The Hapgood lab is currently further exploring these ideas in human explant cervical tissue culture models in MCB, set up by PhD student Ms Roslyn Ray, who spent some time in the UK to transfer the technology. The effects of different contraceptives and HIV-1 on immune function is being investigated, as well as the role of the GR. Results to date suggest that, as for the other models, MPA differentially modulates immune function and HIV-1 replication, in these tissues, as compared to other progestins. Taken together, the basic research by Prof Hapgood and her talented postgraduate students provides strong support for re-evaluation of choice of contraceptive used by women in areas of high risk for infectious diseases, in particular HIV-1.
Crosstalk between Stress and Reproduction pathways:
The Hapgood lab has for several years focussed on a molecular and cellular understanding of how different drugs targeted to other receptors can cross talk with the GR to cause side-effects, as well as how the GR can integrate cell signalling between stress, immune function and reproduction. Recently the Hapgood lab have published a key paper showing how the GR can integrate cell signalling between cortisol and other hormones involved in reproduction, which had wide implications for drugs targeting and integration of cell signalling (Wehmeyer et al., 2014).