application): Neurodegenerative diseases exact a massive toll on human and health care resources. They also pose the fundamental question of the mechanisms underlying selective degeneration of particular neuronal populations. Recent identification of the genes involved in several major neurodegenerative disorders, including Huntington's disease and Alzheimer's disease, represent major advances, but have not yet revealed how the encoded proteins produce cell death. Additional components of the neurodegenerative pathway must be identified. The applicants propose to use Drosophila as a model system to identify proteins required for neuronal degeneration. Both Huntington's disease and Alzheimer s disease are dominantly inherited neurodegenerative disorders most likely produced by toxic actions of the encoded gene products. Appropriate forms of both proteins will be expressed in Drosophila using the GAL4 system that facilitates transgene expression in a variety of defined tissue-specific and temporal patterns. The anatomic and behavioral abnormalities resulting from expression of the human transgenes will be characterized, and a phenotype suitable for generating second site suppressors and enhancers will be defined. Flies will then be mutagenized and genetic modifiers isolated. Mammalian homologues of these Drosophila modifiers will be human disease gene candidates and likely components of mammalian neurodegenerative pathways. The ability of many Drosophila proteins, including several discussed in the current application, to substitute functionally for their mammalian counterparts, suggests close analogies between the two systems. Even seemingly highly unique processes such as hindbrain compartmentalization and learning and memory show remarkable similarities. The basic cell biology of neurodegeneration should prove no exception. The applicant is an M.D./Ph.D. who will have completed a residency in anatomic pathology and subspecialty training in neuropathology prior to the proposed start date. She also holds a doctoral degree in neurobiology. The research will be carried out in a Drosophila laboratory group within the Harvard Medical School. A co-sponsor expert in human molecular genetics and neurodegenerative diseases has been selected to complement the primary laboratory's expertise in Drosophila molecular genetics and development.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AG000880-05
Application #
6642128
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Wise, Bradley C
Project Start
1998-09-30
Project End
2004-12-31
Budget Start
2003-09-01
Budget End
2004-12-31
Support Year
5
Fiscal Year
2003
Total Cost
$103,140
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Colodner, Kenneth J; Feany, Mel B (2010) Glial fibrillary tangles and JAK/STAT-mediated glial and neuronal cell death in a Drosophila model of glial tauopathy. J Neurosci 30:16102-13
Khurana, Vikram; Feany, Mel B (2007) Connecting cell-cycle activation to neurodegeneration in Drosophila. Biochim Biophys Acta 1772:446-56
Larkin, L M; Reynolds, T H; Supiano, M A et al. (2001) Effect of aging and obesity on insulin responsiveness and glut-4 glucose transporter content in skeletal muscle of Fischer 344 x Brown Norway rats. J Gerontol A Biol Sci Med Sci 56:B486-92
Larkin, L M; Halter, J B; Supiano, M A (1996) Effect of aging on rat skeletal muscle beta-AR function in male Fischer 344 x brown Norway rats. Am J Physiol 270:R462-8