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  • Rajesh Thakker, Kate Lines, Kreepa Kooblall, Mark Stevenson
Thakker

about the research

The Academic Endocrine Unit investigates the molecular basis of endocrine and metabolic disorders that principally affect calcium and phosphate homeostasis. 

These disorders may be due to endocrine tumours, kidney defects, or abnormalities of bone metabolism. Thus, the identification of the underlying mechanisms is expected to lead to advances in our understanding of a number of clinical disorders that result in endocrine tumour development, kidney stones and different types of bone disease including rickets and osteoporosis, and inform on novel treatments. Our research can be broadly divided into two main categories, 1) endocrine tumours, and 2) rare kidney and bone disorders.

Endocrine tumours, particularly in the parathyroid, pituitary and pancreas, may develop spontaneously, or in families, and individually or in association with each other, for example, in multiple endocrine neoplasia type 1 (MEN1). MEN1 is an inherited syndrome, caused by loss-of-function mutations of the MEN1 gene (encoding the tumour suppressor protein menin). Patients may develop parathyroid, pituitary and/or pancreatic tumours that over-secrete hormones. MEN1 mutations are also found in sporadic tumours. We aim to better understand the function of menin, and its putative role in epigenetic regulation. Endocrine tumours are usually removed by surgery. However, this is not always possible, and medical therapies are sub-optimal. Improved treatments are therefore needed, and we are investigating epigenetic modifying drugs, which we have shown to reduce endocrine tumour cell proliferation.

The group are also researching rare monogenic kidney and skeletal disorders that include Dent’s disease, Familial juvenile hyperuricaemic nephropathy (FJHN), and Marshall-Smith Syndrome (MSS). Dent’s disease, is associated with rickets, kidney stones and renal failure, and is due to mutations in CLC-5, a chloride-proton antiporter. CLC-5 mutations disrupt endocytosis within kidney tubules resulting in reduced protein reabsorption and we are using cellular models to investigate these processes mechanistically. FJHN is associated with renal fibrosis and is due to mutations in uromodulin. We are studying how uromodulin mutations cause protein misfolding and how this leads to renal fibrosis. MSS, is characterised by abnormal bone formation, and mental and motor retardation, and is caused by mutations in the NFIX gene. We aim to determine the effect of MSS-associated mutations on NFIX functions.

 We therefore aim to build on the current work of the group targeting epigenetics to develop novel therapies for neuroendocrine tumours, and to elucidate the function of NFIX to better understand MSS pathogenesis and identify novel therapies. For neuroendocrine tumour studies the ability of compounds that inhibit the activity of histone modifying proteins will be assessed in reducing cell proliferation in vitro, and reduce NET growth in vivo, both alone and in combination with drugs currently used in the clinic. The mechanisms by which these compounds act will also be investigated, focusing predominantly on the interaction of menin and epigenetic modifications, to gain greater insight into the proteins involved in NET development and growth. For MSS studies our aim is to generate in vitro assays and in vivo mouse models expressing mutant NFIX that more closely resembles the mutations and phenotypes observed in MSS patients. These models will then be used to study the role of NFIX in the pathogenesis of MSS and to identify potential treatments for MSS.

training opportunities

All projects would be based at the Oxford Centre for Diabetes, Endocrinology and Metabolism and would provide training in a wide range of basic molecular biology techniques including Western Blot, PCR, DNA sequencing and immunohistochemistry; cellular biology techniques including cell culture, cell transfections, site directed mutagenesis, proliferation assays, apoptosis assays, flow cytometry analysis and microscopy; as well as the use of in vivo mouse models. Our group also has established international collaborators in drug development and bone morphology.

Students are encouraged to attend the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

publications

Endothelial Cell Tetrahydrobiopterin Modulates Sensitivity to Ang (Angiotensin) II-Induced Vascular Remodeling, Blood Pressure, and Abdominal Aortic Aneurysm. Chuaiphichai S. et al, (2018), Hypertension, 72, 128 - 138

Roles for endothelial cell and macrophage Gch1 and tetrahydrobiopterin in atherosclerosis progression. Douglas G. et al, (2018), Cardiovasc Res, 114, 1385 - 1399

JCAD, a Gene at the 10p11 Coronary Artery Disease Locus, Regulates Hippo Signaling in Endothelial Cells. Jones PD. et al, (2018), Arterioscler Thromb Vasc Biol, 38, 1711 - 1722

A key role for tetrahydrobiopterin-dependent endothelial NOS regulation in resistance arteries: studies in endothelial cell tetrahydrobiopterin-deficient mice. Chuaiphichai S. et al, (2017), Br J Pharmacol, 174, 657 - 671

Effect of irradiation and bone marrow transplantation on angiotensin II-induced aortic inflammation in ApoE knockout mice. Patel J. et al, (2018), Atherosclerosis, 276, 74 - 82