The ciliopathies are a group of >100 overlapping clinical disorders caused by defects in the primary cilium and its anchoring structure, the basal body. Although individually rare, this group contributes significantly to the population genetic disease burden. Fueled in part by genetic discoveries, the primary cilium is now appreciated to be a central component of paracrine signaling regulation, influencing our understanding of numerous developmental processes and disease mechanisms. During the previous funded period, we established the role of basal body proteins in regulating aspects of both canonical and non-canonical Wnt signaling. Using this information, we went on develop assays to probe the mechanistic basis of these observations and to study the effect of mutations found in ciliopathy patients. Our recent studies have also revealed a major, previously unappreciated, role of basal body proteins. We discovered that some basal body proteins regulate the selective proteasome-mediated degradation of signaling components and thus act as a homeostatic regulator of diverse signal transduction cascades. In this renewal, we propose three Aims. First, we will test the hypothesis that the observed proteasomal defects are driven, at least in part, by defective composition of the regulatory components of the proteasome and ask whether such defects are ligand-dependent or independent. Second, based on the hypothesis that proteasomal dysfunction contributes to the signaling phenotypes pathognomonic of ciliopathies, we will ask whether mutations in the 64 proteasomal subunits found in the ciliary proteome can contribute causal or modifying alleles to patients with diverse ciliopathy phenotypes. Finally, our preliminary data have indicated that chemical agonists of the proteasome can ameliorate signaling phenotypes in both cells and live zebrafish embryos, raising the possibility that they might have therapeutic benefit. Therefore, we will investigate the ability of such agonists to attenuate or ameliorate ciliopathy phenotypes in a mouse model. Taken together, our studies will inform the fundamental mechanisms that underpin ciliopathies, potentially providing an orthogonal view of the functions of this organelle, and will provide potential insights that can lay the foundation for clinical trials in humans.

Public Health Relevance

Establishing a role for the basal body in regulating proteasome-dependent degradation will have major consequences on a) understanding of the mechanisms of ciliopathies and b) identifying new causal and modifying loci and alleles. Finally, success in our mouse drug trials will contribute to the development of drug trials in humans.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Therapeutic Approaches to Genetic Diseases (TAG)
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Rasooly, Rebekah S
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Duke University
Anatomy/Cell Biology
Schools of Medicine
United States
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