Henry Krause

MY RESEARCH OVERVIEW  (GO TO SCIENTIFIC OVERVIEW)

Discovering new tools to target metabolic disease

My study of two small but powerful model organisms, the fruitfly and zebrafish, will one day help humans live healthier lives. These organisms have been chosen as a model for examining a group of proteins controlled by hormones such as estrogen and testosterone. Humans have 48 of these so called “nuclear receptors”, but we still don’t know the identities of half of the hormones that regulate them. My lab is working to find out what these are. Once identified, these hormones – or drugs that mimic them – will be used to cure diseases such as obesity, diabetes, atherosclerosis, asthma, depression and many different cancers.

My lab also studies how cellular architecture is controlled by the guided movement of RNA molecules. RNA is a copy of a DNA sequence that is free to move about the cell. Many RNAs carry the codes for protein production. Our genome-wide analysis of RNA localization in the fruit fly has shown that at least 80% of RNAs are targeted to different parts of the cell before being converted into protein. This new level of regulation has a major impact on local functions such as cell shape, growth, movement and function. These processes must also be kept under tight control, otherwise developmental diseases or tumours will ensue.

Being a part of the Donnelly Centre is great. The scientists here are unique in two respects: first, we are fascinated by technology – developing and making use of it; and second, we find ways to use these technologies to survey complete sets of an organism’s genes, proteins or RNAs. Together, these approaches yield never-before-seen results and insights on a global scale. I have been able to make wonderful use of my colleague’s technologies such as chemical compound collections and screening systems to enhance my own lab’s work – an advantage that has transformed my research far beyond where it would otherwise have been.

SCIENTIFIC RESEARCH OVERVIEW

Our lab uses high throughput genomic, proteomic and ribonomic assays to understand fundemental processes of development and disease. We have engineered novel zebrafish and Drosophila model systems into robotic-based screening platforms.

The lab’s current major area of focus is on the 48-member family of human nuclear receptor proteins (NRs). These coordinate homeostatic processes such as cholesterol uptake, steroid metabolism, growth, sexual differentiation, aging and behaviour. Common diseases arising from their malfunction include obesity, diabetes, depression, Alzheimer’s and cancer. NRs are regulated by small diffusible lipid hormones such as steroids (eg estrogen) and lipophilic vitamins (eg Vit D). Their prevalence in disease, and ability to be modulated by small molecules, has made them one of the most successful drug targets. However, many of these drugs still have dangerous side effects, and about half of the NRs are still “orphans” in terms of successful drug targeting and endogenous ligand identification.

We have developed a highly disruptive new drug screening method for nuclear receptors that makes use of the pharmacological and genetic strengths of the zebrafish. We have made transgenic lines representing each of the human NRs that respond to active drugs or hormones by fluorescing green. We also have the ability to purify the activated NRs from the fish to identify bound drugs, hormones or metabolites, as well as protein cofactors. Our screens for new small molecule regulators of these proteins should lead to the production of new and powerful drugs that can treat or prevent these dibilitating diseases.

A second area of focus is on the transport of messenger RNAs to different sites in the cell. We have discovered that this is a major new means by which protein distribution and function is controlled. By analyzing the entire Drosophila genome, we are finding that up to 90% of mRNAs show clear subcellular trafficking prior to translation. Disruption of these subcellular trafficking pathways also results in deregulated cell growth, differentiation and function, resulting in a variety of developmental birth defects, neurological malfunctions and cancers. Bioinformatics studies of our data are showing emerging new trafficking mechanisms, subcellular organelles and new protein and RNA structures and functions.

SELECT PUBLICATIONS

• Spatial profiling of nuclear receptor transcription patterns over the course of Drosophila development. Wilk R, Hu J, Krause HM. G3 (Bethesda). 2013 Jul 8;3(7):1177-89.
• Nitric oxide coordinates metabolism, growth, and development via the nuclear receptor E75. Cáceres L, Necakov AS, Schwartz C, Kimber S, Roberts IJ, Krause HM. Genes Dev. 2011 Jul 15;25(14):1476-85.
• A live zebrafish-based screening system for human nuclear receptor ligand and cofactor discovery. Tiefenbach J, Moll PR, Nelson MR, Hu C, Baev L, Kislinger T, Krause HM. PLoS One. 2010 Mar 22