The objective of this research is to better understand the role of the ciliary central pair in childhood health and disease. Defects in ciliary beating result in a variety of abnormalities, including sinusitis (sinus infection), neonatal respiratory distress, otitis media (ear infection), male infertility, female infertility, hydrocephalus (""""""""water on the brain""""""""), and situs inversus (a reversal of left-right asymmetry). Respiratory and ear infections are common in young children and are usually treated with antibiotics, while neonatal respiratory distress is one of the leading causes of death in newborns. Hydrocephalus is extremely debilitating and potentially fatal if untreated by surgical shunting, and infertility is a major societal concern that impacts families on a regular basis. While all of these disorders are multifactorial, any or all of them can be associated with primary ciliary dyskinesia (PCD), a syndrome that affects approximately one in 16,000 newborn children worldwide and is caused only by defects in motile cilia function. Consequently, this research is of interest to basic scientists, clinicians, and the general public. Although several genes have been implicated in PCD in human patients and mouse models, little is known about how ciliary function is regulated. Mice homozygous for the nm1054 mutation lack primary ciliary dyskinesia protein 1 (Pcdpl), and mice homozygous for the big giant head (bgh) mutation lack sperm flagellar protein 2 (Spef2). Both mutants have PCD, and both proteins localize to the ciliary central pair, enabling further studies focusing on the role of the central pair in ciliary disease. Based on the phenotypes of these mutants, we hypothesize that the central pair regulates the dynein motor force required for proper ciliary beating. We also hypothesize that central pair proteins have a testis-specific function that underlies a distinct pathway required for spermatogenesis. The primary goals of this proposal are to dissect the molecular pathways by which Pcdpl and Spef2 regulate both sperm differentiation and ciliary motility, which will further elucidate the mechanisms perturbed in PCD and its associated disorders.
PCD is a syndrome comprised of several pediatric disorders, some of which can be devastating and even fatal. Improved treatment of PCD and its associated component disorders will require a better understanding of the mechanisms underlying ciliary and flagellar function. This study employs biochemical and cell biological approaches to elucidate the function of proteins lacking in two mouse models of PCD.
|White, Katherine A; Swier, Vicki J; Cain, Jacob T et al. (2018) A porcine model of neurofibromatosis type 1 that mimics the human disease. JCI Insight 3:|
|Anderson, Ruthellen H; Lensing, Cody J; Forred, Benjamin J et al. (2018) Differentiating Antiproliferative and Chemopreventive Modes of Activity for Electron-Deficient Aryl Isothiocyanates against Human MCF-7 Cells. ChemMedChem 13:1695-1710|
|Johnson, Tyler B; Mechels, Keegan; Anderson, Ruth Ellen et al. (2018) Characterization of a recurrent missense mutation in the forkhead DNA-binding domain of FOXP1. Sci Rep 8:16161|
|Brudvig, J J; Cain, J T; Sears, R M et al. (2018) MARCKS regulates neuritogenesis and interacts with a CDC42 signaling network. Sci Rep 8:13278|
|Roux, Kyle J; Kim, Dae In; Burke, Brian et al. (2018) BioID: A Screen for Protein-Protein Interactions. Curr Protoc Protein Sci 91:19.23.1-19.23.15|
|Hussain, Sajjad; Bedekovics, Tibor; Liu, Qiuying et al. (2018) UCH-L1 bypasses mTOR to promote protein biosynthesis and is required for MYC-driven lymphomagenesis in mice. Blood 132:2564-2574|
|Brudvig, J J; Cain, J T; Schmidt-Grimminger, G G et al. (2018) MARCKS Is Necessary for Netrin-DCC Signaling and Corpus Callosum Formation. Mol Neurobiol 55:8388-8402|
|Anderson, Ruthellen H; Kerkvliet, Jason G; Otta, Jaelin J et al. (2018) Generation of a CLTA reporter human induced pluripotent stem cell line, CRMi001-A-1, using the CRISPR/Cas9 system to monitor endogenous clathrin trafficking. Stem Cell Res 33:95-99|
|Lucido, Christopher T; Callejas-Valera, Juan L; Colbert, Paul L et al. (2018) ?2-Adrenergic receptor modulates mitochondrial metabolism and disease progression in recurrent/metastatic HPV(+) HNSCC. Oncogenesis 7:81|
|McKenzie, Casey W; Preston, Claudia C; Finn, Rozzy et al. (2018) Strain-specific differences in brain gene expression in a hydrocephalic mouse model with motile cilia dysfunction. Sci Rep 8:13370|
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