The long-term objective of this proposal is the understanding of the molecular mechanism that creates bending and waveforms of cilia and flagella. To reach this objective studies will be performed to describe the position and function of the inner dynein arms along and across the axonemes of Chlamydomonas flagella. The inner dynein arms produce shear forces at different points along outer doublet microtubules and, therefore, create and maintain axonemal bends. Other axonemal substructures, such as the """"""""dynein regulatory complex"""""""" (drc) and the radial spokes modify the waveforms of the axonemes. In contrast, motors, such as the outer dynein arms, affect the beat frequency of the axonemes. The long term objective will be approached through the following specific aims: 1) identify the position within the axoneme of specific light, intermediate and heavy chains of inner dynein arms. 2) identify the function of specific inner dynein arms in the initiation and propagation of axonemal waveforms. 3) describe the interactions occurring in the ensemble of inner dynein arms, radial spokes and drc at the molecular level. 4) determine whether axoneme assembly depends on active transport of specific inner dynein arm subunits. A model of the inner dynein arm organization along and across the axoneme will be tested by these experimental approaches. The following hypotheses also will be tested: 1) each form of inner dynein arm affects a particular characteristic of axonemal waveforms, 2) the protein centrin provides a calcium-dependent regulation of inner dynein arm activity, 3) proximal inner dynein arm subunits are transported actively to their final destination. The axonemes of Chlamydomonas flagella are an excellent model system for studies of cilia and flagella of complex organisms. They are functionally and morphologically similar to axonemes from a variety of sources. Furthermore, they can be analyzed by genetics. Cilia or flagella are appended to various cell types in the human body such as: epithelial cells lining the respiratory tracts, the oviduct cells, sperm cells and the ependymal cells in the spinal cord. Axonemal dysfunctions in humans may cause respiratory ailments or sterility or the """"""""Kartagener's syndrome"""""""" or hydrocephalus.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM044467-09
Application #
2900738
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1990-04-01
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2001-03-31
Support Year
9
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
Iomini, Carlo; Li, Linya; Mo, Wenjun et al. (2006) Two flagellar genes, AGG2 and AGG3, mediate orientation to light in Chlamydomonas. Curr Biol 16:1147-53
Iomini, Carlo; Tejada, Karla; Mo, Wenjun et al. (2004) Primary cilia of human endothelial cells disassemble under laminar shear stress. J Cell Biol 164:811-7
Iomini, C; Babaev-Khaimov, V; Sassaroli, M et al. (2001) Protein particles in Chlamydomonas flagella undergo a transport cycle consisting of four phases. J Cell Biol 153:13-24
Piperno, G; Siuda, E; Henderson, S et al. (1998) Distinct mutants of retrograde intraflagellar transport (IFT) share similar morphological and molecular defects. J Cell Biol 143:1591-601
Piperno, G; Mead, K (1997) Transport of a novel complex in the cytoplasmic matrix of Chlamydomonas flagella. Proc Natl Acad Sci U S A 94:4457-62
Piperno, G; Mead, K; Henderson, S (1996) Inner dynein arms but not outer dynein arms require the activity of kinesin homologue protein KHP1(FLA10) to reach the distal part of flagella in Chlamydomonas. J Cell Biol 133:371-9
LeDizet, M; Piperno, G (1995) ida4-1, ida4-2, and ida4-3 are intron splicing mutations affecting the locus encoding p28, a light chain of Chlamydomonas axonemal inner dynein arms. Mol Biol Cell 6:713-23
LeDizet, M; Piperno, G (1995) The light chain p28 associates with a subset of inner dynein arm heavy chains in Chlamydomonas axonemes. Mol Biol Cell 6:697-711
Piperno, G; Mead, K; LeDizet, M et al. (1994) Mutations in the ""dynein regulatory complex"" alter the ATP-insensitive binding sites for inner arm dyneins in Chlamydomonas axonemes. J Cell Biol 125:1109-17
Piperno, G; Mead, K; Shestak, W (1992) The inner dynein arms I2 interact with a ""dynein regulatory complex"" in Chlamydomonas flagella. J Cell Biol 118:1455-63

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