New Scholar Award in Aging
Shuji Kishi, M.D., Ph.D.
Dana Farber Cancer Institute, Harvard Medical School

Genetic Approaches for Functional Aging in Zebrafish

Zebrafish (Danio rerio) offer a number of advantages for studying biological and biomedical science. Because embryonic development is external to the mother and the embryos are transparent, zebrafish were initially used as a model system for developmental biology. Recently, zebrafish have become a useful organism for research on a number of common diseases in vertebrates, including cancer, and cardiovascular, neurodegenerative and hematopoietic diseases. Since aging symptoms include susceptibility to several diseases such as cancer predisposition, I intend to utilize zebrafish as a model system of physiological aging and for a pathophysiological study of age-associated diseases.

The mechanisms of the organismal aging process remains a complex enigma to be unveiled. It is poorly understood which genetic elements determine lifespan and how environmental modulations affect senescence in higher organisms such as vertebrates. Although several single gene mutations that regulate lifespan and senescence have been identified in invertebrate organisms such as the worm and fly, it will be essential to assess aging and age-associated diseases in more complex vertebrates to provide rational strategies for therapeutics or interventions, because intrinsic and many environmental factors affect the aging process in higher organisms. So far, mice have served as the only popular vertebrate model system to answer specific questions of the aging process. However, the choice of an appropriate animal model remains one of the most important issues facing various experimental approaches.

Zebrafish have emerged as a powerful model system for functional genetic and genomic approaches to elucidate disease mechanisms, as well as developmental dynamics. In preliminary studies to assess aging phenotypes in zebrafish, I have identified several potential aging biomarkers in an ongoing search for suitable ones on zebrafish aging. By utilizing biological and biochemical aging markers already characterized in normal zebrafish, transgenic analyses and genetic mutant screens can be readily performed. These efforts will help to elucidate the role and molecular mechanisms of common pathways of aging in vertebrates from fish to human, and also will contribute to the discovery of potential drugs applicable to age-associated diseases. Importantly, a large-scale drug screening of small molecules and random mutagenesis for gene discovery, which will provide therapeutic strategies into target diseases, can be readily performed in the zebrafish system. Moreover, in addition to a conventional transgenic approach into zebrafish, I anticipate that other reverse genetic approaches will open other avenues to discovery on aging.

I hypothesize that: (I) reverse genetic approaches using stable and/or conditional transgenesis will contribute to the generation of zebrafish aging models; (II) forward genetic approaches by genome-wide chemical mutagenesis screens in zebrafish can be used to identify an abnormal aging process, implicating mutated genes important in vertebrate senescence; and (III) a subset of the genes, characterized by reverse genetic approaches or discovered by forward genetic approaches, have human counterparts that contribute to development of adult or late-age onset diseases or to one of the premature aging syndromes.

Contact Dr. Kishi.