EMORY UNIVERSITY
Grant: $64,950 - National Institutes of Health - Sep. 30, 2009
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Award Description: 'Functional Substructure of Flagellar Dynein' (3R37GM051173-25S1) This award is an Administrative Supplement from the NIGMS to support our research on cilia and the ciliary dyneins. Based on several advances, the significance of our work on cilia has been greatly expanded in the last several years. Cilia are responsible for diverse and critical motile and sensory functions in the developing and adult human. Defective ciliary assembly or function lead to abnormal Left-Right pattern defects and fatal heart abnormalities, hydrocephaly, skeletal defects, ?primary ciliary dyskinesia? or Kartegener?s syndrome (diseases that manifest themselves in failure in normal respiratory function, brain ventricle function and infertility), blindness and polycystic kidney disease (Christensen et al., 2007; Marshall, 2008; Marshall and Nonaka, 2006; McGrath and Brueckner, 2003; Michaud and Yoder, 2006; Snell et al., 2004; Vogel, 2005; Yoder, 2007). Moreover, recent studies indicate the primary cilium plays a direct role in the signaling pathways that control cell proliferation (Plotnikova et al., 2008; Quarmby and Parker, 2005; Santos and Reiter, 2008; Singla and Reiter, 2006). Importantly, and part of the reason to cite these discoveries is that much of the discovery of conserved genes involved in these functions and diseases derives directly from experimental studies in the model genetic system Chlamydomonas: the recently published computational analysis (Avidor-Reiss et al., 2004; Li et al., 2004) and ciliary proteome (Pazour et al., 2005) have identified a number of disease genes as ciliary components leading to a comprehensive, new view of the cilium that has initiated several translational studies and firmly establish the cilium?s critical role in human biology and human health. Dyneins are ubiquitous molecular motors required for vital cell functions including directed cytoplasmic transport of organelles, protein complexes and viruses (e.g. axonal transport and ?IFT? ? intraflagellar transport), assembly and function of the Golgi and mitotic apparatus and movement of cilia. The major questions include: How does dynein generate force? How is dynein activity regulated? And, how are different dynein isoforms targeted and anchored to cellular cargoes? We aim to answer these questions.
Project Description: We have not yet been funded or recieved an account number, but we were notified that the Administrated Supplement will be awarded. PURPOSE:Our goal is to determine the mechanims that regulate ciliary motility and the dynein motors that drive ciliary movment. As indicated in the original application, the specific aims include: [1] determine how phosphorylation of IC138 regulates I1 dynein activity; [2] identify regulatory domains in IC138, taking advantage of IC138 mutants and phospho-residue mapping and determine the role of IC97 in regulation and assembly of I1 dynein; [3] determine how axonemal signaling proteins, such as the A-kinase anchoring protein RSP3, PKA, CK1 and PP2A, regulate motility. Based on our new results and advances on I1 dynein in cilia (Wirschell et al., 2009; Bower et al., 2009) and on CK1 (Gokhale et al., 2009), we have new opportunities to test our main hypothesis that IC138 phosphorylation and I1 dynein are critical regulators of ciliary bending. EXPRECTED OUTCOMES: These proposed experiments will provide new principles important to cilia, to dynein motors and to signaling in general. Our approaches, experimental system and focus on I1 dynein and will develop a: (i) A general model for regulation of dynein motors. (ii) A mechanism for how I1 dynein regulates ciliary bending. (iii) Furthermore, the IC138 transformants will [a] directly test our model using motility assays and phenotypic analysis of motility and [b] provide an immediate resource for our community and colleagues. (iv) A mechanism for targeting and anchoring of the CK1 class of kinases.
Infrastructure Description: N/A
Jobs Summary: The supplemental support directly helps meet the goals of the Recovery Act by providing extended support for a senior postdoc, Dr. Maureen Wirschell. (100% effort) Dr. Wirschell has the unique experience and skills to immediately continue our studies of I1-dynein assembly and regulation. Keeping a fully trained outstadning postdoc on these projects will provide the expertise needed to pursue these goals in an accurate and timely manner, completing the goals of the supplement within the time frame prescribed in the NIH and NIGMS notices. (Total jobs reported: 0)
Project Status: Not Started
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