(MRC DTP iCASE) Exploring Novel Human Glucocorticoid Response Markers in Children with Adrenal Insufficiency at The University of Manchester on FindAPhD.com

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Dr A Stevens, Dr Philip Murray No more applications being accepted Competition Funded PhD Project (Students Worldwide)

Manchester United Kingdom Artificial Intelligence Bioinformatics Data Analysis Endocrinology Genetics Molecular Biology Computer Science Pharmacy

About the Project

Background:

Adrenal insufficiency remains a significant cause of morbidity and mortality in children with 5-10 adrenal crises per 100 patient years. Patients with hypopituitarism including cortisol insufficiency have an eight-fold increase in mortality compared to those without cortisol insufficiency. Adequate glucocorticoid replacement is therefore key to the prevention of adrenal crisis. Excessive treatment with glucocorticoids must also be avoided as it can lead to growth impairment, weight gain/obesity, high blood pressure, premature cardiovascular disease and osteopenia/osteoporosis.

Current Biomarkers of Glucocorticoid Replacement:

24 hour cortisol profiles: these are expensive and not convenient for patients requiring admission and multiple blood samples. The tissue effects of glucocorticoids are regulated by many local factors including pre-receptor metabolism of glucocorticoids and the interaction of the glucocorticoid receptor with tissue-specific transcription factors. Thus measurements of cortisol fail to capture variation in tissue glucocorticoid sensitivity which is crucial to accurate dosing. Cortisol measurement cannot be used in patients taking oral estrogens due to the effects on cortisol binding globulin.

ACTH can be used to guide treatment in primary AI but is not useful in pituitary or hypothalamic disease. For patients with 21-hydrocyase deficiency measurement of 17-OHP along with androstenedione and testosterone are used as measures of control. Testosterone is not useful in post-pubertal males and both androstenedione and testosterone can be increased in adolescent females with PCOS. Measurement of 17-OHP levels fails to reflect long term replacement and adequate suppression of 17-OHP cannot differentiate treatment which is just right from overtreatment.

Novel Human Glucocorticoid Response Markers:

A multi-omic approach to identification of novel glucocorticoid response markers identified a genomic signature shared between blood and adipose tissue in adults with Addison’s disease related to glucocorticoid exposure. This included 59 genes and one miRNA (miR-122-5p). The genomic signature and miRNA was validated in five in vitro models and three retrospective clinical studies in adults.

Project Aims: To explore the utility of these novel glucocorticoid response markers in a chort of children with adrenal insufficiency of a variety of causes – primary AI (Addison’s disease and congenital adrenal hyperplasia) as well as adrenal insufficiency caused by hypopituitarism. In conjunction with the industrial partner the student will also explore the design of clinical trials of novel modified release glucocorticoids with particular focus on how to assess adequacy of glucocorticoid replacement.

Entry Requirements

Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.

How to Apply

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC Doctoral Training Partnership (DTP) website www.manchester.ac.uk/mrcdtpstudentships

Applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible.

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/

Funding Notes

This is a CASE studentship in partnership with Diurnal Group PLC. Funding will cover UK tuition fee and stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of scholarships that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

1. Chantzichristos D, Svensson PA, Garner T, Glad CA, Walker BR, Bergthorsdottir R, Ragnarsson O, Trimpou P, Stimson RH, Borresen SW, Feldt-Rasmussen U, Jansson PA, Skrtic S, Stevens A, Johannsson G. Identification of human glucocorticoid response markers using integrated multi-omic analysis from a randomized crossover trial. Elife. 2021 Apr 6;10:e62236. doi: 10.7554/eLife.62236.
2. Stevens A, Murray P, De Leonibus C, Garner T, Koledova E, Ambler G, Kapelari K, Binder G, Maghnie M, Zucchini S, Bashnina E, Skorodok J, Yeste D, Belgorosky A, Siguero JL, Coutant R, Vangsøy-Hansen E, Hagenäs L, Dahlgren J, Deal C, Chatelain P, Clayton P. Gene expression signatures predict response to therapy with growth hormone. Pharmacogenomics J. 2021 May 27. doi: 10.1038/s41397-021-00237-5. Online ahead of print.
3. Stevens A, Perchard R, Garner T, Clayton P, Murray P. Pharmacogenomics applied to recombinant human growth hormone responses in children with short stature. Rev Endocr Metab Disord. 2021 Mar;22(1):135-143. doi: 10.1007/s11154-021-09637-1. Epub 2021 Mar 1.
4. Smith HL, Stevens A, Minogue B, Sneddon S, Shaw L, Wood L, Adeniyi T, Xiao H, Lio P, Kimber SJ, Brison DR.
Systems based analysis of human embryos and gene networks involved in cell lineage allocation. BMC Genomics. 2019 Mar 5;20(1):171
5. Paredes R, Kelly JR, Geary B, Almarzouq B, Schneider M, Pearson S, Narayanan P, Williamson A, Lovell SC, Wiseman DH, Chadwick JA, Jones NJ, Kustikova O, Schambach A, Garner T, Amaral FMR, Pierce A, Stevens A, Somervaille TCP, Whetton AD, Meyer S. EVI1 phosphorylation at S436 regulates interactions with CtBP1 and DNMT3A and promotes self-renewal. Cell Death Dis. 2020 Oct 20;11(10):878.