Our laboratory uses the combination of genetics, molecular biology, and informatics to investigate pathways underlying common cardiovascular and metabolic disorders. We exploit natural genetic variation among inbred strains of mice and among human populations to identify novel targets and formulate hypotheses, and we perform validation using experimental perturbations in mice. A major focus has been the interactions underlying commom, complex forms of atherosclerosis, heart failure, and fatty liver disease.
Our laboratory has taken advantage of high throughput biologic technologies, such as transcriptomics, metabolomics, and proteomics, to help develop new approaches to understand complex traits. We have shown that when integrated with natural genetic variation, such multi-omics analyses can be used to model biologic pathways and uncover regulatory mechanisms, an approach known as “systems genetics”. We have recently applied this to better understand host-gut microbiome interactions and how they contribute to cardio-metabolic disease.
During the past 10 years, we have developed a unique mapping approach in mice that is analogous to genome-wide association studies in humans. This approach utilizes a well-characterized population of 100 inbred strains of mice, termed the Hybrid Mouse Diversity Panel (HMDP). A major advantage of this approach is that the resolution is much better than with traditional genetic crosses. It also facilitates studies of gene-by-environment interactions, which are very difficult to address in human populations, and it has important advantages for systems-based approaches which require access to relevant tissues.
Some recent publications that are representative of our approaches are the following:
- Orozco LD, Bennett BJ, Farber CR, Ghazalpour A, Pan C, Che N, Wen P, Qi HX, Mutukulu A, Siemers N, Neuhaus I, Yordanova R, Gargalovic P, Pellegrini M, Kirchgessner T, Lusis AJ. (2012) Unraveling inflammatory responses using systems genetics and gene-environment interactions in macrophages. Cell 151:658-70. PMCID:PMC3513387
- Seldin MM, Koplev S, Rajbhandari P, Vergnes L, Rosenberg GM, Meng Y, Pan C , Phuong TMN, Gharakhanian R, Che N, Mäkinen S, Shih DM, Civelek M, Parks BW, Kim ED, Norheim F, Krishnan KC, Hasin-Brumshtein Y, Mehrabian M, Laakso M, Drevo CA, Koistinen HA, Tontonoz P, Reue K, Cantor RM, Björkegren JLM and Lusis AJ. (2018) A strategy for discovery of endocrine interactions with application to whole-body metabolism. Cell Metab. 27:1138-1155.e6. PMCID: PMC5935137
- Norheim F, Hasin-Brumshtein Y, Vergnes L, Chella Krishnan K, Pan C, Seldin MM, Hui ST, Mehrabian M, Zhou Z, Gupta S, Parks BW, Walch A, Reue K, Hofmann SM, Arnold AP, Lusis AJ. (2019) Gene-by-sex interactions in mitochondrial functions and cardio-metabolic traits. Cell Metab. 29:932-949. PMCID:PMC6447452