scholarly journals Ocular Ciliopathies: Genetic and Mechanistic Insights into Developing Therapies

2019 ◽  
Vol 26 (17) ◽  
pp. 3120-3131 ◽  
Author(s):  
Mahesh Shivanna ◽  
Manisha Anand ◽  
Subhabrata Chakrabarti ◽  
Hemant Khanna
Keyword(s):  
Outer Segment ◽  
Genetic Diseases ◽  
Ciliated Cell ◽  
Anterior Segment ◽  
Treatment Strategies ◽  
Cell Types ◽  
Aqueous Fluid ◽  
Disease Manifestation ◽  
Genetic Components ◽  
Suitable Treatment

Developing suitable medicines for genetic diseases requires a detailed understanding of not only the pathways that cause the disease, but also the identification of the genetic components involved in disease manifestation. This article focuses on the complexities associated with ocular ciliopathies – a class of debilitating disorders of the eye caused by ciliary dysfunction. Ciliated cell types have been identified in both the anterior and posterior segments of the eye. Photoreceptors (rods and cones) are the most studied ciliated neurons in the retina, which is located in the posterior eye. The photoreceptors contain a specialized lightsensing outer segment, or cilium. Any defects in the development or maintenance of the outer segment can result in severe retinal ciliopathies, such as retinitis pigmentosa and Leber congenital amaurosis. A role of cilia in the cell types involved in regulating aqueous fluid outflow in the anterior segment of the eye has also been recognized. Defects in these cell types are frequently associated with some forms of glaucoma. Here, we will discuss the significance of understanding the genetic heterogeneity and the pathogenesis of ocular ciliopathies to develop suitable treatment strategies for these blinding disorders.

scholarly journals Forkhead transcription factor FKH-8 is a master regulator of primary cilia in C. elegans

2021 ◽  
Author(s):  
Rebeca Brocal-Ruiz ◽  
Ainara Esteve-Serrano ◽  
Carlos Mora-Martinez ◽  
Peter Swoboda ◽  
Juan Tena ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Genetic Diseases ◽  
Ciliated Cell ◽  
Cell Types ◽  
Forkhead Transcription Factor ◽  
Master Regulator ◽  
C Elegans ◽  
Direct Activation ◽  
Wide Range ◽  
Motile Cilia

SUMMARYCilia, either motile or non-motile (a.k.a primary or sensory), are complex evolutionary conserved eukaryotic structures composed of hundreds of proteins required for their assembly, structure and function that are collectively known as the ciliome. Ciliome mutations underlie a group of pleiotropic genetic diseases known as ciliopathies. Proper cilium function requires the tight coregulation of ciliome gene transcription, which is only fragmentarily understood. RFX transcription factors (TF) have an evolutionarily conserved role in the direct activation of ciliome genes both in motile and non-motile cilia cell types. In vertebrates, FoxJ1 and FoxN4 Forkhead (FKH) TFs work with RFX in the direct activation of ciliome genes, exclusively in motile cilia cell-types. No additional TFs have been described to act together with RFX in primary cilia cell-types in any organism. Here we describe FKH-8, a FKH TF, as master regulator of the primary ciliome in Caenorhabditis elegans. fkh-8 is expressed in all ciliated neurons in C. elegans, binds the regulatory regions of ciliome genes, regulates ciliome gene expression, cilium morphology and a wide range of behaviours mediated by sensory cilia. Importantly, we find FKH-8 function can be replaced by mouse FOXJ1 and FOXN4 but not by members of other mouse FKH subfamilies. In conclusion, our results show that RFX and FKH TF families act as master regulators of ciliogenesis also in sensory ciliated cell types and suggest that this regulatory logic could be an ancient trait predating functional cilia sub-specialization.

scholarly journals From animal models to patients: the role of placental microRNAs, miR-210, miR-126, and miR-148a/152 in preeclampsia

2020 ◽  
Vol 134 (8) ◽  
pp. 1001-1025 ◽  
Author(s):  
Sonya Frazier ◽  
Martin W. McBride ◽  
Helen Mulvana ◽  
Delyth Graham
Keyword(s):  
Animal Models ◽  
Cell Types ◽  
Rodent Model ◽  
Hypertensive Disorder ◽  
Model Studies ◽  
Genetic Components ◽  
Immune Mediated ◽  
Hypertensive Disorder Of Pregnancy

Abstract Placental microRNAs (miRNAs) regulate the placental transcriptome and play a pathological role in preeclampsia (PE), a hypertensive disorder of pregnancy. Three PE rodent model studies explored the role of placental miRNAs, miR-210, miR-126, and miR-148/152 respectively, by examining expression of the miRNAs, their inducers, and potential gene targets. This review evaluates the role of miR-210, miR-126, and miR-148/152 in PE by comparing findings from the three rodent model studies with in vitro studies, other animal models, and preeclamptic patients to provide comprehensive insight into genetic components and pathological processes in the placenta contributing to PE. The majority of studies demonstrate miR-210 is upregulated in PE in part driven by HIF-1α and NF-κBp50, stimulated by hypoxia and/or immune-mediated processes. Elevated miR-210 may contribute to PE via inhibiting anti-inflammatory Th2-cytokines. Studies report an up- and downregulation of miR-126, arguably reflecting differences in expression between cell types and its multifunctional capacity. MiR-126 may play a pro-angiogenic role by mediating the PI3K-Akt pathway. Most studies report miR-148/152 family members are upregulated in PE. Evidence suggests they may inhibit DNA methylation of genes involved in metabolic and inflammatory pathways. Given the genetic heterogeneity of PE, it is unlikely that a single placental miRNA is a suitable therapeutic target for all patients. Investigating miRNAs in PE subtypes in patients and animal models may represent a more appropriate approach going forward. Developing methods for targeting placental miRNAs and specific placental cell types remains crucial for research seeking to target placental miRNAs as a novel treatment for PE.

scholarly journals A Review of Limbal Stem Cell Deficiency

2019 ◽  
Vol 2 (1) ◽  
pp. e4-e11
Author(s):  
John E. Conto
Keyword(s):  
Stem Cell ◽  
Contact Lenses ◽  
Systemic Disease ◽  
Anterior Segment ◽  
Treatment Strategies ◽  
Limbal Stem Cell Deficiency ◽  
Contact Lens Wear ◽  
Limbal Stem Cell Transplantation ◽  
Limbal Stem Cell ◽  
Amniotic Membranes

Limbal stem cell deficiency (LSCD) can be secondary to multiple etiologies including contact lens wear, chemical or thermal trauma, and systemic disease, any of which can result in the reduction of the number of stem cells or their decreased functionality. Primary LSCD is seen with a variety of congenital anterior segment disorders. Often LSCD can be stabilized and timely diagnosis is the key. The use of topical corticosteroids and artificial tear lubricants, along with treatment of any underlying conditions, and discontinuation of contact lenses are important initial treatment strategies. Advance treatments include amniotic membranes, limbal stem cell transplantation and keratoprostheses.

scholarly journals SLC38A8 mutations result in arrested retinal development with loss of cone photoreceptor specialization

2020 ◽  
Vol 29 (18) ◽  
pp. 2989-3002 ◽  
Author(s):  
Helen J Kuht ◽  
Jinu Han ◽  
Gail D E Maconachie ◽  
Sung Eun Park ◽  
Seung-Tae Lee ◽  
...  
Keyword(s):  
Outer Segment ◽  
Transmembrane Domain ◽  
Retinal Development ◽  
Anterior Segment ◽  
Cone Photoreceptor ◽  
Photoreceptor Outer Segment ◽  
Multi Centre Study ◽  
Photoreceptor Layer ◽  
Foveal Hypoplasia

Abstract Foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis is an autosomal recessive disorder arising from SLC38A8 mutations. SLC38A8 is a putative glutamine transporter with strong expression within the photoreceptor layer in the retina. Previous studies have been limited due to lack of quantitative data on retinal development and nystagmus characteristics. In this multi-centre study, a custom-targeted next generation sequencing (NGS) gene panel was used to identify SLC38A8 mutations from a cohort of 511 nystagmus patients. We report 16 novel SLC38A8 mutations. The sixth transmembrane domain is most frequently disrupted by missense SLC38A8 mutations. Ninety percent of our cases were initially misdiagnosed as PAX6-related phenotype or ocular albinism prior to NGS. We characterized the retinal development in vivo in patients with SLC38A8 mutations using high-resolution optical coherence tomography. All patients had severe grades of arrested retinal development with lack of a foveal pit and no cone photoreceptor outer segment lengthening. Loss of foveal specialization features such as outer segment lengthening implies reduced foveal cone density, which contributes to reduced visual acuity. Unlike other disorders (such as albinism or PAX6 mutations) which exhibit a spectrum of foveal hypoplasia, SLC38A8 mutations have arrest of retinal development at an earlier stage resulting in a more under-developed retina and severe phenotype.

scholarly journals Targeting cancer stem cells in squamous cell carcinoma

2019 ◽  
Vol 2 (3) ◽  
pp. 152-165 ◽  
Author(s):  
Demeng Chen ◽  
Cun-Yu Wang
Keyword(s):  
Stem Cells ◽  
Squamous Cell Carcinoma ◽  
Cancer Stem Cells ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Treatment Strategies ◽  
Cell Types ◽  
Current Treatment ◽  
Small Population

AbstractHead and neck squamous cell carcinoma (HNSCC) is a highly aggressive tumor and the sixth most common cancer worldwide. Current treatment strategies for HNSCC are surgery, radiotherapy, chemotherapy, immunotherapy or combinatorial therapies. However, the overall 5-year survival rate of HNSCC patients remains at about 50%. Cancer stem cells (CSCs), a small population among tumor cells, are able to self-renew and differentiate into different tumor cell types in a hierarchical manner, similar to normal tissue. In HNSCC, CSCs are proposed to be responsible for tumor initiation, progression, metastasis, drug resistance, and recurrence. In this review, we discuss the molecular and cellular characteristics of CSCs in HNSCC. We summarize current approaches used in the literature for identification of HNSCC CSCs, and mechanisms required for CSC regulation. We also highlight the role of CSCs in treatment failure and therapeutic targeting options for eliminating CSCs in HNSCC.

Gastric Adenocarcinoma Arising from Fundic Gland Polyps in a Patient with Familial Adenomatous Polyposis Syndrome

2008 ◽  
Vol 74 (1) ◽  
pp. 79-83 ◽  
Author(s):  
Sean Garrean ◽  
Justin Hering ◽  
Abdul Saied ◽  
Jigna Jani ◽  
N. Joseph Espat
Keyword(s):  
Familial Adenomatous Polyposis ◽  
Gastric Adenocarcinoma ◽  
Intestinal Tract ◽  
Treatment Strategies ◽  
Colorectal Polyps ◽  
Fundic Gland ◽  
Adenomatous Polyposis ◽  
Disease Manifestation ◽  
Fundic Gland Polyps ◽  
Optimal Screening

Familial adenomatous polyposis (FAP) is a rare hereditary syndrome characterized by multiple colorectal polyps and early development of colorectal cancer. Although FAP uniformly involves the large bowel, it may also produce lesions in the stomach and upper intestinal tract. Fundic gland polyps are the most common gastric lesion in FAP. In the general population, these polyps are considered benign and have no malignant potential. However, in FAP patients, fundic gland polyps have been occasionally recognized as precursor lesions from which invasive cancer may develop. Herein, we present a case of gastric adenocarcinoma arising from fundic gland polyps in an FAP patient. We also review reported cases of gastric cancer in FAP and FAP variant patients in an effort to better understand the pathology, clinical course, and optimal screening and treatment strategies for this disease manifestation.

scholarly journals Cell-Selective Regulation of CFTR Gene Expression: Relevance to Gene Editing Therapeutics

Genes ◽  
2019 ◽  
Vol 10 (3) ◽  
pp. 235 ◽  
Author(s):  
Hannah Swahn ◽  
Ann Harris
Keyword(s):  
Gene Expression ◽  
Cystic Fibrosis ◽  
Gene Editing ◽  
Genetic Diseases ◽  
3D Structure ◽  
Three Dimensional ◽  
Cell Types ◽  
Regulatory Elements ◽  
Cftr Gene ◽  
Specific Expression

The cystic fibrosis transmembrane conductance regulator (CFTR) gene is an attractive target for gene editing approaches, which may yield novel therapeutic approaches for genetic diseases such as cystic fibrosis (CF). However, for gene editing to be effective, aspects of the three-dimensional (3D) structure and cis-regulatory elements governing the dynamic expression of CFTR need to be considered. In this review, we focus on the higher order chromatin organization required for normal CFTR locus function, together with the complex mechanisms controlling expression of the gene in different cell types impaired by CF pathology. Across all cells, the CFTR locus is organized into an invariant topologically associated domain (TAD) established by the architectural proteins CCCTC-binding factor (CTCF) and cohesin complex. Additional insulator elements within the TAD also recruit these factors. Although the CFTR promoter is required for basal levels of expression, cis-regulatory elements (CREs) in intergenic and intronic regions are crucial for cell-specific and temporal coordination of CFTR transcription. These CREs are recruited to the promoter through chromatin looping mechanisms and enhance cell-type-specific expression. These features of the CFTR locus should be considered when designing gene-editing approaches, since failure to recognize their importance may disrupt gene expression and reduce the efficacy of therapies.

scholarly journals Calcium control of ciliary arrest in mussel gill cells.

1978 ◽  
Vol 79 (1) ◽  
pp. 110-120 ◽  
Author(s):  
M F Walter ◽  
P Satir
Keyword(s):  
Sodium Phosphate ◽  
Freshwater Mussels ◽  
Ciliated Cell ◽  
Cell Types ◽  
Gill Epithelium ◽  
Ciliated Cells ◽  
Ciliary Membrane ◽  
Gill Cells ◽  
Basal Apparatus ◽  
Triton X

After several hours in 20 mM sodium phosphate and 40 mM KCI (pH 7.4) or similar simple solutions, ciliated cells exfoliate en masse from stripped gill epithelium of freshwater mussels, e.g., Elliptio complanatus. Three types of ciliated cells--lateral (L), laterofrontal (LF), and frontal (F)--can be distiniguished and counted separately in the suspensions. About one-half of the cells of each type remain motile. Motility is unaffected by addition of 10(-5) M A23187 or 10(-2) M Ca+2 added separately, but when ionophore and Ca+2 are added together, ciliary beat is largely arrested. Treatment of the cells with Triton X-100 (Rohm & Haas Co., Philadelphia, Pa.) results in a total loss of motility as the ciliary membrane becomes disrupted. Such models can be reactivated by addition of ATP and Mg+2. All ciliated cell types are reactivated to about the same extent. At least 80% of the activity of the untreated preparation returns. Ca+2-EGTA buffers added to the reactivating solutions permit titration of free Ca+2 concentration vs. percent motility. Activity is unchanged for all cell types at Ca+2 less than 10(-7) M; at 10(-6) Ca+2, L cilia of all cell types are arrested differentially, whereas at Ca+2 greater than 10(-4) M most cilia of all cell types are arrested. We conclude: (a) that increasing cytoplasmic Ca+2 is directly responsible for ciliary arrest, (b) that the readily reversible physiological arrest response of the L cilia in the intact gill is caused by a rise in free Ca+2 in narrow limits from ca. 5 x 10(-7) M to ca. 8 x 10(-7) M, and (c) that the site which is sensitive to Ca+2 is part of the ciliary axoneme or the basal apparatus.

Genomic Analisys of Notch Mutations in a Case of Alagille Syndrome with Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5338-5338
Author(s):  
Simona Bernardi ◽  
Paola Tononi ◽  
Sergio Marin Vargas ◽  
Giulio Bassi ◽  
Paul Takam Kamga ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Anterior Segment ◽  
Alagille Syndrome ◽  
University Hospital ◽  
Pulmonary Artery Stenosis ◽  
Notch 1 ◽  
Germline Mosaicism ◽  
Genetic Components

Abstract Alagille syndrome (ALGS), or arteriohepatic dysplasia, is a congenital multisystem disease due to Notch signalling pathway mutations, most commonly affecting JAGGED-1 (ALGS type 1), and more rarely NOTCH-2 (ALGS type 2), leading to hepatic, lung, renal and ocular dysfunction (chronic cholestasis, peripheral pulmonary artery stenosis, dysplastic kidneys pigmentary retinopathy), and skeletal abnormalies (minor vertebral segmentation, characteristic facies, posterior embryotoxon/anterior segment defects). ALGS is an autosomal dominant disease, but it is characterized also by variable penetrance and clinical expression and somatic/germline mosaicism. A 20-year-old man with ALGS was admitted to the University Hospital of Verona because of pancytopenia. Following analyses led to the diagnosis of Philadelphia chromosome/bcr-abl-negative, CD10-positive, B-lineage acute lymphoblastic leukemia (common B-ALL). In order to identify the genetic components involved in this complex phenotype, we sequenced the exome of a bone marrow sample collected from the patient. By genome interpretation with Knome pipeline applied to the reference genome UCSC hg19, we found missense variants both in NOTCH-2 (E38K) and JAGGED-1 (P871R) genes that are mainly involved in the syndrome, although their effect on protein function was predicted not to be deleterious. However, we detected putative damaging mutations in genes such as PAX5 (R38H) and NOTCH-1 (K1821N), which might be strongly related to the observed disease. In fact, PAX5 is a member of PAX protein family of transcription factors implicated into regulation of early development that binds NOTCH-2 and likely altering its functionality. On the other hand, NOTCH-1 is involved in cell growth and proliferation and thus the predicted alteration of function of the corresponding protein may have an important role in neoplastic transformation. Disclosures Martinelli: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; ARIAD: Consultancy.

scholarly journals Development of Viral Vectors for Gene Therapy for Chronic Pain

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Yu Huang ◽  
Xin Liu ◽  
Lanlan Dong ◽  
Zhongchun Liu ◽  
Xiaohua He ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Chronic Pain ◽  
Viral Vectors ◽  
Treatment Strategies ◽  
Opioid Analgesics ◽  
Cell Types ◽  
Health Concern ◽  
Specific Cell ◽  
New Treatment ◽  
The Individual

Chronic pain is a major health concern that affects millions of people. There are no adequate long-term therapies for chronic pain sufferers, leading to significant cost for both society and the individual. The most commonly used therapy for chronic pain is the application of opioid analgesics and nonsteroidal anti-inflammatory drugs, but these drugs can lead to addiction and may cause side effects. Further studies of the mechanisms of chronic pain have opened the way for development of new treatment strategies, one of which is gene therapy. The key to gene therapy is selecting safe and highly efficient gene delivery systems that can deliver therapeutic genes to overexpress or suppress relevant targets in specific cell types. Here we review several promising viral vectors that could be applied in gene transfer for the treatment of chronic pain and further discuss the possible mechanisms of genes of interest that could be delivered with viral vectors for the treatment of chronic pain.

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