Human disease is frequently treated without detailed knowledge of the molecular mechanisms underlying disease pathogenesis. As researchers have made inroads into understanding the pathogenesis of human disease, targeted therapies based on these molecular insights have led to quantum improvements in human health. For example, elucidation of the role of the low density lipoprotein receptor in cholesterol homeostasis (PubMed link to Brown and Goldstein review) led to the development of HMG-CoA reductase inhibitors, which have revolutionized the treatment of atherosclerotic heart disease and saved countless lives. Similarly, the identification of the BCR-ABL oncoprotein as the causative mutation in chronic myelogenous leukemia (CML) engendered the discovery of Gleevec, an oral BCR-ABL inhibitor that has transformed the way CML is treated (Gleevec review). These and other examples illustrate the potential benefit to human health of developing novel disease treatments based on a detailed understanding of disease pathogenesis.
The advent of next-generation sequencing and genotyping technologies has accelerated the discovery of hundreds of candidate disease genes that may play roles in the pathogenesis of common diseases such as cancer, diabetes, and heart disease. Understanding how these candidate genes may contribute to disease pathogenesis will undoubtedly lead to the development of pioneering therapies that will change paradigms of modern medicine. However, determining the biological function of these candidate disease genes remains a daunting task. Although mammalian models of human disease have been and will remain indispensable research tools in the functional characterization of candidate disease genes, the complexity of mammalian systems can limit the efficiency of this approach. The use of more expeditious experimental approaches would accelerate both the functional characterization of candidate disease genes as well as the development of targeted disease therapies.
We aspire to reveal the molecular basis of human disease, with the long-term goal of making discoveries that lead to the development of better ways to prevent, diagnose, and treat human disease. We are pursuing this goal using a multifaceted approach:
1. We exploit the experimental manipulability of the nematode C. elegans to identify and characterize novel conserved genes encoding components of signaling pathways relevant to human disease. Based on experiments in C. elegans, we develop hypotheses about how these genes function.
2. We test these hypotheses using biochemical, molecular biological, and cell biological approaches in mammalian cell culture.
3. We determine the role of these genes in disease pathogenesis by database mining for gene- and pathway-specific mutations or polymorphisms associated with human disease and by studying the effect of manipulating gene and pathway activity in mouse models of human disease.
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Many molecules and pathways implicated in human disease pathogenesis are structurally and functionally conserved in C. elegans (review on C. elegans orthologs of human disease genes). By taking full advantage of the anatomical simplicity and experimental manipulability of C. elegans, one can rapidly gain insight into the biology of such molecules and pathways and extrapolate these findings to mammalian systems. In this way, the use of C. elegans as a model system can accelerate our understanding of the molecular basis for human disease by allowing us to bypass technical obstacles that are inherent to mammalian experimental models.
Our current research focus is a C. elegans insulin-like growth factor (IGF) pathway that controls metabolism, longevity (see reviews by Cynthia Kenyon and Adam Antebi), and entry into an alternative larval stage called dauer (see the WormBook chapter on dauer and Adam Antebi's review on dauer). We are exploring mechanisms of regulation of the FoxO transcription factor DAF-16, which is the major target of C. elegans IGF signaling. FoxO transcription factors have recently been shown to act as tumor suppressors in mice (Paik et al., 2007) and to play a major role in regulating metabolism in mammalian liver (Matsumoto et al., 2007; Dong et al., 2008), suggesting that pharmacologic manipulation of FoxO activity may be a useful approach to develop novel treatments for cancer and diabetes. Notably, the seminal work that established FoxO as a target of IGF signaling emerged from genetic analysis in C. elegans (Ogg et al., 1997; Lin et al., 1997), underscoring the utility of our approach.
We have discovered a novel conserved hormonal pathway, the EAK pathway, that controls development and longevity in C. elegans by regulating the activity of nuclear DAF-16/FoxO (Hu et al., 2006; Zhang et al., 2008). Since FoxO functions as a tumor suppressor and metabolic regulator in mice, we anticipate that the EAK pathway may play roles in regulating metabolism and cell proliferation in mammals and may be dysregulated in common human diseases such as cancer and Type 2 diabetes. We are actively pursuing the elucidation of how the EAK pathway regulates nuclear DAF-16/FoxO activity in C. elegans, and we are developing reagents that will allow us to study the potential role of the conserved proteins EAK-2 and EAK-7 in regulating metabolism and cell proliferation in mice. Ultimately, we will examine the effect of the EAK pathway on disease pathogenesis using established mouse models of cancer and Type 2 diabetes.
Hypothetical model of IGF/EAK pathway interactions in C. elegans. EAK-2 promotes steroid hormone synthesis in endocrine (upper) cells, and these hormones regulate DAF-16/FoxO target gene expression in target (lower) cells via DAF-12/LXR. When both pathways are active (left panel), AKT-1 phosphorylation of DAF-16/FoxO results in its sequestration in the cytoplasm, and liganded DAF-12/LXR does not promote dauer arrest. When both pathways are inactive (right panel), DAF-16 and unliganded DAF-12 converge on target gene promoters to regulate gene expression.
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