Drug Development and Disease Diagnostics
Molecular basis of drug targets and diseases

144 College Street
Toronto ON M5S 3M2

Area of Research

Carolyn Cummins studies nuclear receptors and their role in the development of diabetes, obesity and other metabolic diseases, with the goal of identifying potential therapeutic targets in disease pathways and developing drugs to prevent or treat these conditions. In particular, her research focuses on the glucocorticoid receptor, liver X receptor (LXR) and peroxisome proliferator-activated receptor (PPAR).

Research Challenge

Metabolism refers to the set of life-sustaining chemical reactions that convert food into energy, with hormones carefully balancing the processes that use and store energy. Many of these hormones act on nuclear receptors – a family of transcription factors that bind to DNA and alter gene expression when activated. Poor diet, genetics or even certain drugs may affect hormone levels and their binding to nuclear receptors and other signalling pathways, resulting in metabolic diseases, such as diabetes or obesity. For example, some glucocorticoid drugs, which are steroid hormones that bind to nuclear receptors, are taken for anti-inflammatory purposes but as a side effect may increase the user’s risk of developing type 2 diabetes. There is still much to be understood about how nuclear receptors and hormone levels regulate signalling pathways, which makes it challenging to develop effective drugs to treat metabolic diseases.

Proposed Solution

The Cummins lab is uncovering the signalling pathways of nuclear receptors and what happens at the molecular and physiological level when signalling goes wrong. One project investigates how the nuclear receptor LXRß, which is important in regulating carbohydrate metabolism, can be targeted to restore the disrupted glucose signalling caused by glucocorticoid therapies. Another project looks at how a compound derived from a waste by-product of the Brazilian cashew nut industry activates the nuclear receptor PPAR and can potentially be used to treat diseases like fatty liver, hyperlipidemia and insulin resistance. The Cummins lab also investigates the relationship between nuclear receptor signalling and RNA splicing (a process by which a cell increases protein diversity) and the role of cholesterol and LXRs in vascular disease, and the team is developing a new approach to quantify all 48 nuclear receptors at the protein level.

Impact To Date

Cummins' work has led to the development and preclinical testing of several drugs for the treatment of metabolic diseases. Her team discovered that nuclear hormone signalling can induce alternative splicing during the process of translating genetic information into proteins, and their pioneering work investigating this previously unknown relationship is highlighting new potential drug targets. Furthermore, their findings on global and genome-wide effects of nuclear receptor signalling will have important impact on future research and drug development.



Keywords: molecular, genetic tools, ligand-activated transcription factors, molecular mechanisms, signalling pathways, therapeutic targets, diabetes, obesity, co-regulation proteins, animal physiology