Overall research directions
Aging is an inexorable homeostatic failure of complex but largely unknown etiology that leads to increased vulnerability to disease (e.g. cancer, diabetes atherosclerosis, neurodegeneration) with enormous consequences on the quality of individual lives and the overall cost to society. Until recently, the daunting complexity of the aging process, the conspicuous lack of tools to study it, and a dearth of experimentally tractable model systems have greatly hindered any hypothesis-driven reductionist approaches to understanding the molecular basis of aging, particularly in mammals. A number of syndromes (Cockayne syndrome, trichothiodystrophy and XPF-ERCC1) and associated mouse models with defects in genome maintenance pathways show prominent features of progeria suggesting that a defective cellular response to DNA damage accelerates aging, likely in a tissue-specific manner. Here, we aim to use tissue-specific mouse models of accelerated aging and naturally aged mice as an experimentally tractable system to delineate the responses to DNA damage that are most pertinent to segmental progeria and natural aging as well as to identify the natural defence mechanisms that attempt to counteract age-related pathology and prolong lifespan.
Current work is focused on
1. The impact of genome instability on pathways associated with longevity, aging and age-related pathology: The accumulation of unrepairable DNA lesions in the genome hampers the process of transcription by blocking RNA Pol II, thereby revealing the role of transcriptional instability with advancing age. We aim to identify common genome-wide expression patterns between a number of TCR-defective, progeroid mice and mice that carry (tissue-specific) constitutive defects in transcription. We are using a number of advanced molecular, genomics and imaging approaches to investigate the role of transcriptional instability in progeria and age-related pathology.
2. The impact of progeroid mutations on tumour development: This project aims at investigating the fine balance between cancer protection and accelerated aging. We will assess the individual impact of progeroid mutations (e.g. Csb m/m and Xpd TTD ) in well-characterized in vivo tumour models. We utilize a unique set of well-characterized progeroid mouse models coupled to advanced genomics techniques as well as cell biological and biochemical approaches to identify genes and pathways associated with longevity that might also be crucial in the early, intermediate and advanced stages of carcinogenesis. This approach might provide us both with mechanistic insight into the complex process of tumorigenesis as well as gene targets for its experimental modulation in the future.
3. Genome instability and tissue-specific progeria: This project aims at investigating age-related processes driven by genome instability in a tissue-specific manner. To do this, we take advantage of the loxP/Cre recombinase technology to restrict DNA repair deficiency in a single type of tissue while leaving the remaining part of the organism intact.
4. Development of advanced bioinformatics approaches to integrate functional genomics data with and biological endpoints in cancer and aging. The realization of our current research approach dictates the implementation of a robust, advanced panel of bioinformatics curation tools that will give structure and meaning to the underlying information so that this can be queried by non bioinformatics-related scientists. To do this, we aim to develop an available online, highly interactive and easily curable database incorporating the underlying high throughput biological data along with the deduced information on gene, protein networks and biological processes with biochemical, molecular biology and animal physiology parameters in a single integrated platform in our lab.