The central problems addressed in the proposed research are how the centrosome is organized, how it duplicates once per cell cycle, and how we go from the "parts list" for the organelle to a more complete understanding of how it works. The centrosome nucleates microtubules and helps to organize those microtubules to create useful arrays, including the mitotic spindle and the cilium. Work from my lab and others over the last 20 years at Stanford has identified molecules involved in microtubule nucleation, the central regulators of centrosome duplication, important structural proteins involved in duplication, and control mechanisms that govern centrosome number and link the centrosome and the cilium. Interest in the centrosome is strong because of the correlation between centrosome abnormalities and the development of cancer, and because of the role of the centrosome in ciliopathies, diseases related to primary cilium function, and microcephaly, a defect in neuronal development. The proposed experiments make use of the strengths that we have developed in reagents and assays for studying centrosome structure, function and duplication in different experimental systems. We have chosen to focus on the process in animal cells, tissues and extracts as they are the systems most relevant to our desire to understand the human centrosome in normal cell division, and in disease.
Three specific aims are addressed in this proposal:
Specific Aim 1 - Identify and characterize the interactions that define the centriole "origin of duplication" Specific Aim 2 - Characterize the mode of action of Mdm1, a unique negative regulator of centriole duplication.
Specific Aim 3 - Create centriole-less mammalian cells to address the function of the centrosome in the cell cycle, cell signaling, and nuclear functions.
The centrosome is a component of the cell that sits at the center of a network of fibers, microtubules that perform work within the cell and receive and respond to signals. The centrosome is present in exactly one copy per cell and it duplicates every cell cycle, along with the chromosomes. Defects in the centrosome are associated with cancer, and developmental disorders including defects in brain development.
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