A5013904885- Genetic and Kidney Cyst Diseases
- Congenital heart defects research
- Congenital Heart Disease Studies
- Cystic Fibrosis Research Advances
- Coronary Artery Anomalies
- Tracheal and airway disorders
- Renal and related cancers
- Neuroscience of respiration and sleep
- Neonatal Respiratory Health Research
- Connexins and lens biology
- Hedgehog Signaling Pathway Studies
- Protist diversity and phylogeny
- Pluripotent Stem Cells Research
- Genetic Syndromes and Imprinting
- Microtubule and mitosis dynamics
- Congenital Anomalies and Fetal Surgery
- Cerebrospinal fluid and hydrocephalus
- Tissue Engineering and Regenerative Medicine
- Cellular transport and secretion
- Heat shock proteins research
- Molecular Biology Techniques and Applications
- Mining Techniques and Economics
- Spacecraft and Cryogenic Technologies
- Respiratory Support and Mechanisms
- Cardiovascular and Diving-Related Complications
James Cook University
2022-2025
Birla Institute of Technology and Science - Hyderabad Campus
2024
University of Pittsburgh
2010-2023
Alcoa (Australia)
2023
UNSW Sydney
2015-2018
ARC Centre of Excellence in Advanced Molecular Imaging
2018
Great Western Hospitals NHS Foundation Trust
2017
National Imaging Facility
2015-2016
Children's Hospital of Pittsburgh
2013
Jackson Laboratory
2013
Previous studies have indicated an intimate linkage between gap junction and adherens formation. It was suggested this could reflect the close membrane-membrane apposition required for In NIH3T3 cells, we observed colocalization of connexin43 (Cx43alpha1) protein with N-cadherin, p120, other N-cadherin-associated proteins at regions cell-cell contact. We also found that Cx43alpha1, were coimmunoprecipitated by antibodies to either or various proteins. These findings suggest Cx43alpha1...
Patients with congenital heart disease (CHD) and heterotaxy show high postsurgical morbidity/mortality, some developing respiratory complications. Although this finding is often attributed to the CHD, airway clearance left-right patterning both require motile cilia function. Thus, ciliary dysfunction (CD) similar that of primary dyskinesia (PCD) may contribute increased complications in patients.We assessed 43 CHD patients for CD. Videomicrocopy was used examine motion nasal tissue, nitric...
Connexin 43 knockout (Cx43α1KO) mice have conotruncal heart defects that are associated with a reduction in the abundance of cardiac neural crest cells (CNCs) targeted to heart. In this study, we show CNCs can respond changing fibronectin matrix density by adjusting their migratory behavior,with directionality increasing and speed decreasing density. However, compared wild-type CNCs, Cx43α1KO reduced speed, while overexpressing Cx43α1 from CMV43 transgenic increased speed. Altered integrin...
The motive forces for ciliary movement are generated by large multiprotein complexes referred to as outer dynein arms (ODAs), which preassembled in the cytoplasm prior transport axonemal compartment. In humans, defects structural components, docking complexes, or cytoplasmic assembly factors can cause primary dyskinesia (PCD), a disorder characterized chronic airway disease and laterality. By using combined high resolution copy-number variant mutation analysis, we identified ARMC4 mutations...
Heterotaxy, a birth defect involving left-right patterning defects, and primary ciliary dyskinesia (PCD), sinopulmonary disease with dyskinetic/immotile cilia in the airway are seemingly disparate diseases. However, they have an overlapping genetic etiology mutations genes, reflection of common requirement for motile clearance. While PCD is monogenic recessive disorder, heterotaxy has more complex, largely non-monogenic etiology. In this study, we show novel dynein gene DNAH6 can cause...
Planar cell polarity (PCP) regulates alignment required for collective movement during embryonic development. This requires PCP/PCP effector proteins, some of which also play essential roles in ciliogenesis, highlighting the long-standing question role cilium PCP. Wdpcp, a PCP effector, was recently shown to regulate both ciliogenesis and movement, but underlying mechanism is unknown. Here we show Wdpcp can by direct modulation actin cytoskeleton. These studies were made possible recovery...
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder associated with defects and situs inversus totalis, the complete mirror image reversal of internal organ (positioning). A variable incidence heterotaxy, or irregular situs, also has been reported in PCD patients, but it not known whether this elicited by PCD-causing genetic lesion. We studied mouse model recessive mutation Dnahc5, dynein gene commonly mutated PCD. Analysis homozygous mutant embryos from 18 litters...
Knockout mice deficient in the gap junction gene connexin43 exhibit developmental anomalies associated with abnormal neural crest, primordial germ cell, and proepicardial cell migration. These migration defects are due to a loss of directional movement, actin stress fiber organization polarized morphology. To elucidate mechanism by which Cx43 regulates polarity, we used wound closure assays mouse embryonic fibroblasts (MEFs) examine morphology movement. Studies using from knockout (Cx43KO)...
Meckel-Gruber syndrome (MKS) is a recessive disorder resulting in multiple birth defects that are associated with mutations affecting ciliogenesis. We recovered mouse mutant mutation the Mks1 gene (Mks1(del64-323)) caused 260-amino-acid deletion spanning nine amino acids B9 domain, protein motif unknown function conserved two other basal body proteins. showed that, wild-type cells, was localized to mother centriole from which cilium generated. However, Mks1(del64-323) not centriole, even...
Connexin 43 knockout (Cx43 KO) mice exhibit conotruncal malformations and coronary artery defects. We observed epicardial blisters in the Cx43 KO hearts that suggest defects epithelial-mesenchymal transformation(EMT), a process generates vascular progenitors. Analysis using three-dimensional collagen gel invasion assay showed cells are less invasive that, unlike wild-type cells, they fail to organize into thin vessel-like projections. Examination of Wt1 as an marker revealed disorganized...
The ciliary kinase NEK8 plays a critical role in situs determination and cystic kidney disease, yet its exact function remains unknown. In this study, we identify ANKS6 as target activator of NEK8. requires for localizing to the inversin compartment (IC) activates by binding domain. Here demonstrate functional importance interaction through analysis two novel mouse mutations, Anks6Streaker Nek8Roc. Both display heterotaxy, cardiopulmonary malformations kidneys, syndrome also characteristic...
Bves is an integral membrane protein with no determined function and homology to proteins outside of the Popdc family. It widely expressed throughout development in myriad organisms. Here, we demonstrate interaction between guanine nucleotide exchange factor T (GEFT), a GEF for Rho-family GTPases. This represents first identification any that has direct physical member GEFT are shown colocalize adult skeletal muscle. We also exogenous expression reduces Rac1 Cdc42 activity levels while not...
Forward genetic screens with ENU (N-ethyl-N-nitrosourea) mutagenesis can facilitate gene discovery, but mutation identification is often difficult. We present the first study in which an ENU-induced was identified by massively parallel DNA sequencing. This causes heterotaxy and complex congenital heart defects mapped to a 2.2-Mb interval on mouse chromosome 7. Massively sequencing of entire 2 single-base substitutions, one intergenic region second causing replacement highly conserved...
Complex congenital heart disease (CHD) is often seen in conjunction with heterotaxy, the randomization of left-right visceral organ situs. However, link between cardiovascular morphogenesis and patterning not well understood. To elucidate role development, we examined situs anomalies CHD mice a loss function allele Dnaic1, dynein protein required for motile cilia patterning. Dnaic1 mutants were found to have nodal patterning, but they immotile. Half had concordant comprising solitus or...
Rationale: Patients with congenital heart disease heterotaxy exhibit a high prevalence of abnormal airway ciliary motion and low nasal nitric oxide, characteristics associated primary dyskinesia, reflection the role motile cilia in clearance left–right patterning.Objectives: To assess potential broader clinical significance dysfunction disease, we assessed versus respiratory symptoms patients or without heterotaxy.Methods: broad spectrum were recruited (n = 218), 39 heterotaxy. Nasal oxide...
Congenital heart disease (CHD) has a multifactorial pathogenesis, but genetic contribution is indicated by heritability studies. To investigate the spectrum of CHD with we conducted forward screen in inbred mice using fetal echocardiography to recover mutants CHD. Mice are ideally suited for these studies given that they have same four-chamber cardiac anatomy substrate CHD.Ethylnitrosourea mutagenized were ultrasound-interrogated clinical ultrasound system, and fetuses suspected...
Recent studies identified a previously uncharacterized gene C5ORF42 (JBTS17) as major cause of Joubert syndrome (JBTS), ciliopathy associated with cerebellar abnormalities and other birth defects. Here we report the first Jbts17 mutant mouse model, Heart Under Glass (Hug), recovered from forward genetic screen. Exome sequencing Hug S235P missense mutation in homolog JBTS17 (2410089e03rik). mutants exhibit multiple defects typical ciliopathies, including skeletal dysplasia, polydactyly,...
An objective, computational method to quantitatively identify ciliary motion in digital videos of cells from patients with ciliopathies can be used for diagnosis.
Tracheal loss is a source of significant morbidity for affected patients with no acceptable solution. Interest in engineering tracheal transplants has created demand small animal models orthotopic transplantation. Here, we examine the use decellularized graft murine model replacement. Fresh or tracheas harvested from age-matched female donor C57BL/6 mice were transplanted into syngeneic recipients. Tracheas using repeated washes water, 3% Triton X-100, and 3 M NaCl under cyclic pressure...
Ciliary motion defects cause defective mucociliary transport (MCT) in primary ciliary dyskinesia (PCD). Current diagnostic tests do not assess how MCT is affected by perturbation of motion. In this study, we sought to use micro-optical coherence tomography (μOCT) delineate the mechanistic basis cilia PCD genes functional categorization Tracheae from three mouse models were analyzed using μOCT characterize and measure MCT. We developed multiple measures activity, integrated these measures,...