Kisspeptin is a 54 amino acid hypothalamic peptide hormone that activates KISS1 receptors. However, the physiological function of kisspeptin is not confined to the hypothalamus, as the hormone and its receptor are expressed in various tissues, including the endocrine pancreas and liver. Kisspeptin has been shown to stimulate insulin secretion from beta cells. More recent evidence suggests that activation of hepatic KISS1 receptors can ameliorate non-alcoholic fatty liver disease (NAFLD). Thus, kisspeptin represents an exciting target for the treatment of diabetes, obesity and NAFLD. However, as with many peptide hormones, kisspeptin is proteolytically processed into several smaller fragments. Uncovering the mechanisms involved in kisspeptin degradation together with its role in the progression of metabolic diseases, could help reveal, an as yet untapped, therapeutic promise.
Therefore, we will address the following research questions:
1) What impact do kisspeptin peptides have on pancreatic beta-cell function? We will determine full enzymatic degradation profile of kisspeptin and assess secretory and functional effects of kisspeptin peptides on pancreatic beta-cells.
2) Can long-acting enzyme resistant forms of kisspeptin be generated that maintain biological activity? Using knowledge gained from question 1, we will synthesise enzyme resistant forms of kisspeptin and confirm bioactivity. The most promising analogues will be progressed to in vivo studies for examination of effects on satiety and glucose homeostasis.
3) What impact will enzymatically stable kisspeptin peptides have on metabolic control? Preclinical therapeutic effectiveness of lead kisspeptin peptides will be studied in models of diabetes.
In addition, we will employ mice fed a high fat diet to assess how the hepatic KISS1R can prevent liver fat accumulation. Expected Results: Based on the literature, KISS1R modulation will positively impact beta-cell function. We are also confident that sustained activation of hepatic KISSR will exert direct measurable benefits in NAFLD.
Please note: Applications for more than one PhD studentship are welcome, however if you apply for more than one PhD project within Biomedical Sciences, your first application on the system will be deemed your first-choice preference and further applications will be ordered based on the sequential time of submission. If you are successfully shortlisted, you will be interviewed only on your first-choice application and ranked accordingly. Those ranked highest will be offered a PhD studentship. In the situation where you are ranked highly and your first-choice project is already allocated to someone who was ranked higher than you, you may be offered your 2nd or 3rd choice project depending on the availability of this project.
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