In many organ systems, cells projecting hundreds of beating cilia, called multiciliate cells, produce a vigorous fluid flow that transports biological materials along luminal surfaces. Multiciliate cells populate the respiratory airways, the reproductive tract, and the ventricles of the brain, where the flow they produce has significant implications for human health. A key process in achieving directed flow is to align beating cilia along a common planar axis, requiring mechanisms that orient the rotational axis of the basal body at the base of each cilium. This process is known to be initiated by the planar cell polarity pathway, and to involve flow-based cues and elements of the cytoskeleton, but the mechanisms that align cilia direction are largely unknown. To address this issue, one approach is define the genetic pathways that drive the differentiation of multiciliate cells, and to use these pathways to identify novel factors that underlie cilia orientation. Specifically, this approach addresses the fact that the basal bodies in a multiciliate cell are highly specialized compared to those found in other ciliated cells, but the molecular bases of these specialization remain undefined. Using this approach, basal body factors involved in cilia orientation will be identified, and their role in producing directed fluid flow will be characterized. The factors studied include a new basal body associated protein required for maturating cilia orientation, proteins that comprise a basal body appendage called the ciliary rootlet, and candidate proteins that have been identified based on their structural features, and the fact that their expression is associated with multiciliate cell differentiation. The proposed studies will generate new insights into the cell specific components that allow basal bodies in multiciliate cells to mediate directed fluid flow, and lay the foundation for understanding how flow can fail in human diseases such as primary ciliary dyskinesia.

Public Health Relevance

Multiciliate cells play important roles in human health by generating fluid flow in the brain, lung and reproductive tract, but the mechanisms that enable these cells to orient their beating cilia are poorly understood. To study these mechanisms, the proposed research will focus on new components of the basal body required for cilia orientation, including a family of poorly characterized coiled-coil proteins. Results from these studies will ai in the understanding of human diseases that affect ciliated epithelia, such as the ciliary defects that occurs in primary ciliary dyskinesia and Kartagener's syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM076507-09
Application #
8632799
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Hoodbhoy, Tanya
Project Start
2005-09-21
Project End
2017-11-30
Budget Start
2013-12-15
Budget End
2014-11-30
Support Year
9
Fiscal Year
2014
Total Cost
$446,200
Indirect Cost
$216,200
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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