Biology subjects

Karunakaran, K. B.

Publications and source records attributed to Karunakaran, K. B..

6 recordsLinked to original sources

bioRxiv2022

GPX4-associated Sedaghatian Type Spondylometaphyseal Dysplasia: A Protein Interactome Perspective

Spondylometaphyseal dysplasia, Sedaghatian type (SMDS) is a rare and lethal skeletal dysplasia inherited in an autosomal recessive manner and caused by mutations in GPX4. In order to expand the functional landscape of this poorly studied disorder and accelerate the discovery of biologically insightful and clinically actionable targets, we constructed SMDS-centric and GPX4-centric protein-protein interaction (PPI) networks, augmented with novel protein interactors predicted by our HiPPIP algorithm. The SMDS-centric networks included those that showed the interconnections of GPX4 with other putative SMDS-associated genes and genes associated with other skeletal dysplasias. The GPX4-centric network showed the interconnections of GPX4 with genes whose perturbation has been known to affect GPX4 expression. We discovered that these networks either contained or were enriched with genes associated with specific SMDS pathophenotypes, tissue-naive/fetus-specific functional modules and genes showing elevated expression in brain and/or testis similar to GPX4. We identified 7 proteins as novel interactors of GPX4 (APBA3, EGR4, FUT5, GAMT, GTF2F1, MATK and ZNF197) and showed their potential biological relevance to GPX4 or SMDS. Comparative transcriptome analysis of expression profiles associated with chondroplasia and immune-osseous dysplasia versus drug-induced profiles revealed 11 drugs that targeted the neighborhood network of GPX4 and other putative SMDS-associated genes. Additionally, resveratrol, which is currently being tested against a skeletal dysplasia in a clinical trial, was identified as another potential candidate based on the proximity of its targets to GPX4.

developmental biology↗

bioRxiv2022

Drug Contraindications in Comorbid Diseases: a Protein Interactome Perspective

Adverse drug reactions (ADRs) are leading causes of death and drug withdrawals and frequently cooccur with comorbidities. However, systematic studies on the effects of drugs in comorbidities are lacking. Drug interactions with the cellular protein-protein interaction (PPI) network give rise to ADRs. We selected 6 comorbid disease pairs, identified the drugs used in the treatment of the individual diseases A and B- 44 drugs in anxiety and depression, 128 in asthma and hypertension, 48 in chronic obstructive pulmonary disease and heart failure, 58 in type 2 diabetes and obesity, 58 in Parkinsons disease and schizophrenia, and 84 in rheumatoid arthritis and osteoporosis - and categorized them based on whether they aggravate the comorbid condition. We constructed drug target networks (DTNs) and examined their enrichment among genes in disease A/B PPI networks, expressed across 53 tissues and involved in ~1000 pathways. To pinpoint the biological features characterizing the DTNs, we performed principal component analysis and computed the Euclidean distance between DTN component scores and feature loading values. DTNs of disease A drugs not contraindicated in B were affiliated with proteins common to A/B networks or uniquely found in the B network, similarly regulated common pathways, and disease-B specific pathways and tissues. DTNs of disease A drugs contraindicated in B were affiliated with common proteins or those uniquely found in the A network, differentially regulated common pathways, and disease A-specific pathways and tissues. Hence, DTN enrichment in pathways, tissues, and PPI networks of comorbid diseases will help identify drugs contraindications in comorbidities.

bioinformatics↗

bioRxiv2021

Mispatterned motile cilia beating causes flow blockage in the epileptic brain

Beating of motile cilia at the brain ventricular surface generates rapid flow in an evolutionary conserved pattern mediating the transport of cerebrospinal fluid, but its functional importance has yet to be demonstrated. Here we show disturbance of this transport may contribute to seizure susceptibility. Mice haploinsufficient for FoxJ1, transcription factor regulating motile cilia exhibited cilia-driven flow blockage and increased seizure susceptibility. Mutations in two epilepsy-associated kinases, Cdkl5 and Yes1, in mice resulted in similar cilia-driven flow blockage and increased seizure susceptibility. We showed this arises from disorganized cilia polarity associated with disruption in the highly organized basal body anchoring meshwork. Together these findings suggest mispatterning of cilia-generated flow may contribute to epilepsy and thus might account for seizures unresponsive to current seizure medications. One sentence summaryEpilepsy is associated with disturbance of cilia motion and mispatterning of fluid transport in the brain ventricles.

neuroscience↗

bioRxiv2021

iPSC modeling shows uncompensated mitochondrial mediated oxidative stress underlies early heart failure in hypoplastic left heart syndrome

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect with 30% mortality from heart failure (HF) in the first year of life, but why only some patients suffer early-HF and its cause remain unknown. Modeling using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) showed early-HF patient iPSC-CM have increased apoptosis, redox stress, and failed antioxidant response. This was associated with mitochondrial permeability transition pore (mPTP) opening, mitochondrial hyperfusion and respiration defects. Whereas iPSC-CM from patients without early-HF had hyper-elevated antioxidant response with increased mitochondrial fission and mitophagy. Single cell transcriptomics showed dichotomization by HF outcome, with mitochondrial dysfunction and endoplasmic reticulum (ER) stress associated with early-HF. Importantly, oxidative stress and apoptosis associated with early HF were rescued by sildenafil inhibition of mPTP opening or TUDCA suppression of ER stress. Together these findings demonstrate a new paradigm for modeling clinical outcome in iPSC-CM, demonstrating uncompensated mitochondrial oxidative stress underlies early HF in HLHS.

cell biology↗

bioRxiv2018

Mesothelioma Interactome with 367 Novel Protein-Protein Interactions

Malignant pleural mesothelioma (MPM) is an aggressive cancer of the thorax with a median survival of one year. We constructed an MPM interactome with over 300 computationally predicted PPIs and over 1300 known PPIs of 62 literature-curated genes whose activity affects MPM. Known PPIs of the 62 MPM associated genes were derived from BioGRID and HPRD databases. Novel PPIs were predicted by applying the HiPPIP algorithm, which computes features of protein pairs such as cellular localization, molecular function, biological process membership, genomic location of the gene, gene expression in microarray experiments, protein domains and tissue membership, and classifies the pairwise features as interacting or non-interacting based on a random forest model. To our satisfaction, the interactome is significantly enriched with genes differentially expressed in MPM tumors compared with normal pleura, and with other thoracic tumors. The interactome is also significantly enriched with genes whose high expression has been correlated with unfavorable prognosis in lung cancer, and with genes differentially expressed on crocidolite exposure. 28 of the interactors of MPM proteins are targets of 147 FDA-approved drugs. By comparing differential expression profiles induced by drug to profiles induced by MPM, potentially repurposable drugs are identified from this drug list. Development of PPIs of disease-specific set of genes is a powerful approach with high translational impact - the interactome is a vehicle to piece together an integrated view on how genes associated with MPM through various high throughput studies are functionally linked, leading to clinically translatable results such as clinical trials with repurposed drugs. The PPIs are made available on a webserver, called Wiki-Pi MPM at http://severus.dbmi.pitt.edu/wiki-MPM with advanced search capabilities.\n\nOne Sentence SummaryMesothelioma Interactome with 367 novel protein-protein interactions may shed light on the mechanisms of cancer genesis and progression

cancer biology↗

bioRxiv2018

Potentially repurposable drugs for schizophrenia identified from its interactome

From the schizophrenia drug-target interactome,1 we studied the drugs that targeted multiple proteins in the interactome, or those that target proteins with many targets, or those that target novel (computationally predicted) interactors of schizophrenia associated proteins. In schizophrenia, gene expression has been described as a measurable aspect of the disease reflecting the action of risk genes. We studied each of the selected drugs using the NextBio software suite, and shortlisted those that had a negative correlation with gene expression of schizophrenia. This analysis resulted in 12 drugs whose differential gene expression (drug versus normal) had an anti-correlation with differential expression for schizophrenia (disorder versus normal). Some of these drugs were already being tested for their clinical activity in schizophrenia and other neuropsychiatric disorders. Several proteins in the protein interactome of the targets of several of these drugs were associated with various neuropsychiatric disorders. The network of genes which were differentially expressed on drug treatment, and had an anti-correlation with gene expression in schizophrenia, were significantly enriched in pathways relevant to schizophrenia etiology and GWAS genes associated with traits or diseases that had pathophysiological overlap with schizophrenia. Drugs that are structurally similar to the shortlisted drugs, or targeted the same genes as these drugs, have also demonstrated clinical activity in schizophrenia and other related disorders. This integrated computational analysis may help translate insights from the schizophrenia drug-protein interactome to clinical research - an important step, especially in the field of psychiatric drug development, facing a high failure rate.

neuroscience↗