EASTBIO: Understanding the role of STC2 in regulation of skeletal muscle growth and maintenance

This fully funded, 4-year PhD project is part of a competition funded by the BBSRC EASTBIO Doctoral Training Partnership.

About a third of elderly admissions to long-term health care facilities are due to frailty and inability to perform daily living activities. With the growing demographics of the elderly in Western societies, understanding the mechanisms governing skeletal muscle mass and function becomes increasingly important.

Insulin-like growth factor 1 (IGF1) is a potent autocrine/paracrine promotor of myogenic cell growth, maintenance, and survival. The IGF1 binding to the extracellular domain of IGF1 receptor (IGF1R) of muscle fibres triggers a cascade of intracellular signalling events culminating in upregulation of protein synthesis and downregulation of protein breakdown. However, skeletal muscles also secrete a set of regulatory proteins which can change the interstitial availability of bioactive IGF1. Among the key regulators are the IGF binding proteins (IGFBPs) which possess higher affinity to IGF1 than IGF1R. Therefore most of the IGF1 in the interstitium of muscle fibres is sequestered to the IGF1:IGFBP complex. Two other secreted regulators are pappalysin, PAPP-A, and stanniocalcin-2, STC2. The IGF1:IGFBP complex cannot interact with the IGF1R, but PAPP-A is a specialised proteinase able to break down the complex releasing the bioactive IGF1. This function of PAPP-A, however, is lost upon binding of the STC2 protein. Recent studies conducted in our lab indicate that STC2 plays a significant role in determining muscle mass in humans and animal models.

The project aims to study the mechanisms of the STC2 effects on skeletal muscle. It will be achieved by developing small synthetic macrocyclic peptides that would interfere with the formation of a complex between the PAPP-A and STC2. Based on the crystal structure of the PAPP-A:STC2 complex we will identify the likely binding areas and computationally predict a sequence and 3D structure of macrocyclic peptides which could inhibit the STC2 binding to PAPP-A. We then will synthesize a library of macrocyclic peptides. Macrocyclic peptides are stable and therefore can be used in vivo where the linear peptides are rapidly broken down by proteinases. We first will screen the library peptides for their ability to interfere with the formation the PAPP-A:STC2 complex. Then selected peptides will be examined for their ability to protect the proteolytic capacity of PAPP-A in the presence of STC2 and to upregulate the IGF1R signalling. The developed peptides will provide a tool for manipulation of the regulatory mechanisms impacting availability of biologically active IGF1 allowing to study the role of autocrine/paracrine regulation in the maintenance of skeletal muscle mass and function.

For further project information please contact the lead project supervisor by selecting the first listed name at the top of this advert and sending your enquiry.

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ELIGIBILITY:

Applicants should hold a minimum of a 2:1 UK Honours degree (or international equivalent) in a relevant subject. Those with a 2:2 UK Honours degree (or international equivalent) may be considered, provided they have (or are expected to achieve) a Distinction or Commendation at master’s level.

We encourage applications from all backgrounds and communities, and are committed to having a diverse, inclusive team.

All students must meet the eligibility criteria as outlined in the UKRI guidance on funding for postgraduate training and development. This guidance should be read in conjunction with the Terms and conditions for training funding – UKRI.

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APPLICATION PROCEDURE:

• Please visit this page for full application information: https://biology.ed.ac.uk/eastbio/how-to-apply
• Please send your completed EASTBIO application form, along with academic transcripts and certificates to pgrs-admissions@abdn.ac.uk
• Please ensure that two references are submitted by the deadline using the EASTBIO reference form (available here). If the references are not included with your application, they must be sent directly to pgrs-admissions@abdn.ac.uk with the subject line: "EASTBIO Reference – [Your Name]".
• It is the applicant’s responsibility to ensure that references are submitted by the deadline (17^th January). We will not request academic references on your behalf.
• Please ensure you submit all the required information and documentation. Due to workload constraints, we are unable to follow up on missing documents or process incomplete applications.
• If you require any additional assistance in submitting your application or have any queries about the application process, please don't hesitate to contact us at pgrs-admissions@abdn.ac.uk