Dr. Collins' laboratory seeks to identify and understand the function of genes involved in a range of human diseases. His group is also developing animal models of genetic disorders to test potential therapeutic approaches.
A significant project that Dr. Collins directs focuses on Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic disorder characterized by rapid premature aging. HGPS patients typically die from cardiovascular complications in their teens. Dr. Collins' laboratory recently discovered that a point mutation in the lamin A gene (LMNA) activates a cryptic splice donor, resulting in shortening of the normal version of the encoded protein by 50 amino acids near the C-terminus. They also found that HGPS is associated with significant changes in the shape of the nucleus; these structural defects worsen as HGPS cells age in culture. The severity of nuclear changes correlates with an increase in the mutant protein, called progerin and introducing progerin into normal cells induces the same nuclear changes. Cellular biological analysis implicates progerin in disrupting the normal process of mitosis. More recent investigation of normal human fibroblasts has demonstrated small amounts of progerin are present in normal cell populations, potentially giving valuable insight into the process of normal aging.
The lamin A protein is normally farnesylated at its C-terminus, which apparently helps target the prelamin to the inner surface of the nuclear membrane. A subsequent protease cleavage releases this C-terminal fragment, allowing lamin A to join other proteins in the scaffold that lies just under the nuclear membrane. Progerin is able to be farnesylated, but cannot be cleaved, rendering it permanently anchored in the nuclear membrane, sequestering other proteins and functioning as a dominant negative. Cell-culture experiments in the Collins laboratory have shown that farnesyltransferase inhibitors (FTIs) can significantly ameliorate the nuclear-shape abnormalities seen in HGPS cells.
Because most progeria patients are in extremely fragile health, there are few opportunities to conduct human trials of potential therapies. Dr. Collins' group has developed an animal model of progeria by reengineering human LMNA to carry the HGPS mutation, and inserting it into the germline of a mouse. The mouse develops normally, without progeroid features in skin, hair, or bone, but demonstrates progressive cardiovascular disease that closely resembles the disease seen in HGPS patients. Specifically, these mice exhibit progressive loss of vascular smooth muscle cells in the media of their large arteries. Using the mouse model as a resource for screening potential therapies, the Collins laboratory has demonstrated that FTI treatment not only prevents the onset of cardiovascular disease in young mice but also reduces the progression of the cardiovascular defects upon treatment of older mice. This research has complemented other data in support of a clinical trial administering FTIs to HGPS patients.
The Collins laboratory is also applying positional-cloning techniques to more difficult, non-Mendelian conditions. In a major long-term project involving researchers at the Finnish National Public Health Institute, the University of Michigan, the University of Southern California, and the University of North Carolina, Dr. Collins and his collaborators are studying over 20,000 individuals to identify susceptibility factors for type 2 diabetes (T2D). The FUSION project (Finland — United States Investigation Of NIDDM) began with linkage studies of affected sib pairs, and then moved on to perform a genome-wide association study (GWAS) on a total of 1,200 cases and 1,200 controls using the Illumina 317K genome-wide single-nucleotide polymorphism (SNP) panel. Several interesting associations were tested in stage 2 analysis of a larger number of case and control samples. In combination with data shared from other large association studies of T2D,18 susceptibility loci were identified. Subsequently the FUSION project has become an integral part in several worldwide consortia studying T2D and quantitative traits. To date these consortia have identified over 30 susceptibility loci for T2D and hundreds of loci affecting glucose, BMI, and lipid quantitative traits.
Many of these variants are associated with impaired insulin secretion or processing, and the vast majority reside in non-coding portions of the genome. These data suggest that altered regulatory function in the pancreatic islet may play an important role in T2D pathophysiology. Using ChIP-seq technology, the Collins lab is now investigating the islet epigenome to identify regulatory elements that are necessary for normal islet function and which, when altered, may lead to disease. Characterizing the entire repertoire of human islet regulatory elements will enhance our understanding of gene regulation in the human islet and should provide critical insight into the molecular mechanisms involved in diabetes susceptibility.
Recent seminal work has also identified a role for microRNAs (miRNAs) in lipid and glucose metabolism, but the extent of their influence in metabolic homeostasis is unknown. The Collins lab is studying the underlying mechanism of function of miRNA targeting to establish the importance of miRNAs in regulating metabolic processes. The focus of this study is to systematically characterize miRNAs and miRNA regulation in pancreatic islets and other tissues relevant to T2D.
Despite the findings of these large association studies the majority of T2D heritability remains to be discovered. The Collins laboratory is using hybridization selection of targeted regions of the genome and next generation sequencing techniques on DNA pools to identify rare variants of larger effect in T2D associated genes that might be contributing to the heritability of T2D.
Finally, the Collins laboratory is taking a bold step into the analysis of gene-environment interactions. Allergic asthma is the most common form of asthma and is the product of allergen exposure and underlying genetic susceptibility. The lab is investigating gene-environment interactions in allergic asthma using a physiological model of exposure to house dust mite allergen (HDMA) in which mice are sensitized and challenged with HDMA. This model is being investigated in a panel of genetically diverse mice (The Collaborative Cross), to identify genes that modulate asthma by positional cloning. The results from this study will be shared with collaborators in several epidemiologic research groups in order to translate the findings from mice to humans.
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Last Reviewed: November 8, 2012