Browsing by Subject "MicroRNAs"
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Item Genetic characterization of comorbidity patterns in aging associated diseases using integrative genomics(2019-08) Pathak, Gita A.; Phillips, Nicole R.; Planz, John V.; Barber, Robert C.; Zhou, Zhengyang; Gryczynski, IgnacyThe aging population in the US continues to grow at an exponential rate estimated to reach more than 90 million by 2060. The coexistence of two or more diseases (comorbidity) is prevalent in ages 65 years and above, and the number of comorbidities increases with age. The genetic factors underlying presence and absence of comorbidities is a severely understudied research domain. Alzheimer's disease (AD) is a type of dementia affecting 5.5 million people with an average age of diagnosis at 70 years. Hypertension is a coexisting condition in 60% AD individuals, also known as direct comorbidity. On the other hand, cancer is reported to be inversely comorbid with AD; individuals with cancer history have been reported to have lower risk of AD and vice versa. Furthermore, individuals with cancer history are diagnosed with long term side effects of radiation therapy — radiotoxicity. Twin-based studies have reported that certain gene variants are associated with radiotoxicity phenotypes with a heritability of 66%. This study proposes to investigate genetic factors associated with the direct and inverse comorbidity of AD with hypertension and cancer, and proctitis — a radiotoxicity phenotype observed in survivors of prostate cancer. The study aims to integrate gene variants, derived-gene expression and copy number variation (CNV), followed by functional and pathway-based prioritization of observed findings. We used genome-wide and cerebral spinal fluid profile to investigate presence of hypertension with AD to evaluate individual-level differences, followed by targeted investigation of neighboring gene expression profiles of identified variants. We found several novel genes associated with AD-hypertension comorbidity. The investigation between AD and cancer identified regions in chromosomes 4, 5 and 19 that are targeted by miRNA-17 family along with other miRNAs reported to be inversely expressed and play opposite role in pathogenicity of both diseases. The SNP-derived transcriptomic profile between AD and cancer highlighted involvement of sirtuin signaling. The findings together indicate involvement of mitochondrial and metabolic dysregulation which possibly contribute in differences of the epithelial-mesenchymal-transition. The SNP-derived expression and CNV association with proctitis highlighted genes involved in DNA-repair and mitochondrial ROS damage pathways.Item miRNA Profiling of Human Optic Nerve Head Astrocytes Exposed to Cyclic Stretch(2021-05) Rangan, Rajiv S.; Tovar-Vidales, Tara; Clark, Abbot F.; Liu, YangGlaucoma is a leading cause of irreversible blindness. Vision loss results from the degeneration and death of retinal ganglion cells (RGCs) and their axons. The primary risk factor for glaucoma is increased intraocular pressure (IOP) (2). Elevated IOP results in aberrations in the biomechanical properties of ocular tissues - including the transmission of biomechanical stretch through the reticulated, fibroelastic region of the optic nerve head (ONH) known as the lamina cribrosa (LC) (6). Cells of the LC are sensitive to biomechanical stretch and respond to increased stretch and pressure to promote the excessive synthesis of extracellular matrix (ECM) proteins and ECM remodeling (15,17). These responses promote a fibrotic environment within the LC that can cause mechanical damage to the axons of RGCs. ONH astrocytes represent one of the major cell types of the LC and are believed to contribute significantly to pathological ECM remodeling at the LC during glaucoma (11). ONH astrocytes also demonstrate a dysregulated pattern of protein expression when exposed to stretch (17). The mechanism that underlies this stretch-induced, aberrant dysregulation is unknown. MicroRNA (miRNA) dysregulation may represent one of the mechanisms contributing to the differential protein expression patterns seen in ONH astrocytes exposed to stretch. In this study we examine the miRNA profiles of ONH astrocytes exposed to cyclic stretch.Item The Role of Transforming Growth Factor Beta 2 Signaling and MicroRNAs in Optic Nerve Head Remodeling(2020-08) Lopez, Navita N.; Clark, Abbot F.; Tovar-Vidales, Tara; Liu, Yang; Pang, Iok-HouPrimary open-angle glaucoma (POAG) is a prevalent age-related neurodegenerative disease of the visual system. There are functional and morphological changes in the retina, optic nerve head (ONH) and brain that lead to an irreversible loss of vision. POAG is characterised by degeneration of retinal ganglion cells (RGC), thinning of the neuro-retinal rim and structural deformation of the ONH. The primary site of injury is the lamina cribrosa, which is a fibro-elastic connective tissue that supports the ONH and unmyelinated RGC axons as they exit the intraocular space. Pathological changes to the lamina cribrosa include posterior displacement of the lamina cribrosa, loss of trophic support, and remodeling of the extracellular matrix (ECM). An important growth factor associated with tissue remodeling is TGFb2. TGFb2 activates the SMAD-dependent TGFb2 pathway and increases transcription of several ECM genes including collagen, fibronectin and crosslinking enzymes. In POAG, the levels of TGFb2 are increased in the lamina cribrosa and is associated with excess deposition of ECM molecules. This study proposes to investigate the intermediary mechanisms that lead to tissue remodeling. microRNAs (miRNAs) regulate gene expression by inhibiting protein translation. We hypothesized that miRNAs are dysregulated in POAG and in response to TGFb2, which leads to excess ECM synthesis and tissue remodeling. We isolated primary human ONH astrocytes and lamina cribrosa cells from POAG and normal donor eyes. We used miRNA PCR arrays to determine differentially expressed miRNAs in POAG and TGFb2 treated cells. Several anti-fibrotic miRNAs were downregulated, including downregulation of miR-29c-3p in POAG and TGFb2 treated lamina cribrosa cells, and downregulation of miR-200b-3p in TGFb2 treated ONH astrocytes. To validate mRNA targets and determine the functional role of differentially expressed miRNAs, we modulated miRNA biology using miRNA mimics and inhibitors. Overexpression of miR-29c-3p and miR-200b- decreased the expression of ECM proteins. Treatment with TGFb2 increased the expression of collagens and fibronectin and overexpression of miR-29c-3p and miR-200b-3p decreased this effect, suggesting that miR-29c-3p and miR-200b-3p regulate the TGFb2 signaling pathway. It is possible that increased TGFb2 is responsible for tissue remodeling through inhibition of anti-fibrotic miRNAs and a subsequent increase in ECM synthesis.