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Ciliopathies

Cilia are conserved cellular structures that are nearly ubiquitous in the vertebrate body plan. Although first reported by Antonie van Leeuwenhoek over 200 years ago, it was not until the turn of the 21st century that the extensive roles of this complex cellular structure emerged. Through highly collaborative efforts of many laboratories worldwide, we and others have demonstrated that cilia are key mediators of extracellular cues such as morphogenetic signaling that are critical to proper development and homeostasis. We now know that a repertoire of ~1,000 proteins, the ciliary proteome, are required for correct ciliogenesis and ciliary function, and it is therefore not surprising that disruption of any one of these components can give rise to human genetic disorders termed ciliopathies. Our researchers have a long-standing interest in understanding the genetic architecture of these clinically distinct but overlapping disorders; in the mechanistic dissection of ciliary function in discrete spatiotemporal contexts; and our long-term goal is to develop novel therapeutic strategies aimed to ameliorate or at least prolong the onset of symptoms.

Our ciliopathy research employs a multidisciplinary approach involving genetic analysis of humans with either rare Mendelian or common complex traits likely underscored by a ciliary defect. We use murine and zebrafish models coupled to robust cell-based assays to quantitatively assess ciliary output. Through interactions and collaborations with academic colleagues, patient support groups, and partners from the pharmaceutical industry, we recruit and study the genetic architecture and pathomechanisms of patients with a variety of ciliopathies. Numerous clinical features of the rare ciliopathies, such as psychiatric illness and obesity, are common phenotypes in the general population. We and others have hypothesized that increased mutational burden in ciliary genes can increase the risk for such disorders [25543293]. To investigate this possibility, our researchers used a combination of targeted resequencing of ciliary genes in human cohorts combined with animal models and cell-based assays to establish how specific genetic lesions can lead to neuroanatomical and behavioral alterations that may be relevant to schizophrenia, autism, and obesity [18762586 and 25937446].

Genetic Architecture Of Rare Ciliopathies
Consistent with the broad roles of cilia in the vertebrate body plan, ciliary and basal body defects have been causally linked with at least 15 discrete disorders in humans, caused by mutations in >80 causal genes. Although each disorder, such as Bardet-Biedl syndrome, Meckel-Gruber syndrome, Joubert syndrome, Nephronopthisis, or Primary Ciliary Dyskinesia are individually rare (~1/100,000 to 1/200,000) as many as 100 additional independent clinical entities have been proposed as ciliopathies [22632799]. The advancement of next generation sequencing in recent years has propelled causal gene discovery [24746959, 25869670, and 23849778] and has also provided a platform to uncover genetic modifiers [19430481]. Using sequencing or copy number variant analysis of research participant samples coupled to in vivo studies in zebrafish, our Center aims to understand the genetic architecture of disease by mapping mutational burden to ciliary functional modules such as the BBSome, transition zone, and intraflagellar transport complexes [21258341].

Cilla And Cell Signaling
A major role of the cilium is to act as a chemo-, mechano- and photosensor. Cilia also mediate communication between extra- and intra-cellular signaling effectors not only during development, but also during regenerative and homeostatic processes. Comprehensive study of ciliary mutants ranging from mouse to zebrafish have implicated a prominent role for cilia in signaling paradigms including Shh, Wnt, and Notch. Coupled to robust in vitro assays, we have demonstrated that signaling effectors function at the cilium in response to certain environmental cues [17906624 and 24691443]. Our ongoing research goals are to understand the detailed molecular mechanisms by which ciliary proteins interact in signaling transduction, and to understand the tissue-specific and context-dependent phenomena that result in variable disease phenotypes [21725307].

Therapeutic Development
Recent technological improvements have empowered the efficient manipulation of gene expression and the genome itself. Using a combination of RNAi and CRISPR in cells and zebrafish embryos, our researchers are leading the search for the identification of suppressors of ciliopathies, in other words, genes whose ablation or attenuation might have therapeutic benefit to the phenotypes driven by ciliary dysfunction. Our work shows early promise with the identification of suppressors for a subset of ciliopathies, which have in turn opened possibilities for the testing of lead therapeutic compounds. We aspire to systematize this approach for numerous disorders for which we might have the opportunity to provide ameliorating or therapeutic leads.