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Physiological Genomics

Gregory N Ruegsegger, Ryan G Toedebusch, Joshua F Braselton, Thomas E Childs, Frank W Booth
Peak oxygen consumption (V̇O2peak) strongly predicts morbidity and mortality better than other established risk factors, yet mechanisms associated with its age-associated decline are unknown. Our lab has shown that V̇O2peak first begins to decrease at the same age of 19-20 weeks old in both sedentary and wheel-running, female Wistar rats (Toedebusch et al., Physiol Genomics. 48:101-15, 2016). Here, we employed a total systemic approach using unsupervised interrogation of mRNA with RNA-sequencing. The purpose of our study was to analyze transcriptomic profiles from both sedentary (SED) and wheel-running (RUN) conditions as a strategy to identify pathways in the left ventricle that may contribute to the initial reductions in V̇O2peak occurring between 19 and 27 weeks of age...
December 2, 2016: Physiological Genomics
Stefanie Y Tan, Hannah C Little, Xia Lei, Shuoyang Li, Susana Rodriguez, G William Wong
Secreted hormones play pivotal roles in tissue crosstalk to maintain physiologic blood glucose and lipid levels. We previously showed that C1q/TNF-related protein 12 (CTRP12) is a novel secreted protein involved in regulating glucose metabolism whose circulating levels are reduced in obese and insulin-resistant mouse models. Its role in lipid metabolism, however, is unknown. Using a novel heterozygous mouse model, we show that the loss of a single copy of the Ctrp12 gene (also known as Fam132a and adipolin) affects whole-body lipid metabolism...
November 4, 2016: Physiological Genomics
Lakshmi Kuttippurathu, Biswanath Patra, Daniel Cook, Jan B Hoek, Rajanikanth Vadigepalli
Chronic ethanol intake impairs liver regeneration through a system-wide alteration in the regulatory networks driving the response to injury. Our study focused on the initial phase of response to 2/3(rd) partial hepatectomy (PHx) to investigate how adaptation to chronic ethanol intake affects the genome-wide binding profiles of the transcription factors C/EBP-β and C/EBP-α. These factors participate in complementary and often opposing functions for maintaining cellular differentiation, regulating metabolism, and governing cell growth during liver regeneration...
November 4, 2016: Physiological Genomics
Sophie Calderari, Malika Diawara, Alois Garaud, Dominique Gauguier
MicroRNAs (miRNAs) are intracellular and circulating molecular components contributing to genome expression control through binding mRNA targets, which generally results in downregulated mRNA expression. One miRNA can target several mRNAs and one transcript can be targeted by several miRNAs, resulting in complex fine tuning of regulation of gene networks and signaling pathways. miRNAs regulate metabolism, adipocyte differentiation, pancreatic development, β-cell mass, insulin biosynthesis, secretion and signaling and their role in diabetes and obesity is emerging...
November 4, 2016: Physiological Genomics
Samina Akbar, Anthony Pincon, Marie-Claire Lanhers, Thomas Claudepierre, Catherine Corbier, Lynn Gregory-Pauron, Catherine Malaplate-Armand, Athanase Visvikis, Thierry Oster, Frances T Yen
Perturbations of lipid homeostasis manifest as dyslipidemias and obesity, which are significant risk factors for atherosclerosis and diabetes. Lipoprotein receptors in the liver are key players in the regulation of lipid homeostasis, among which the hepatic lipolysis stimulated lipoprotein receptor, LSR, was recently shown to play an important role in the removal of lipoproteins from the circulation during the postprandial phase. Since heterozygous LSR+/- mice demonstrate moderate dyslipidemia and develop higher body weight gain in response to high-fat diet as compared to littermate LSR+/+ controls, we questioned if LSR heterozygosity could affect genes related to hepatic lipid metabolism...
October 27, 2016: Physiological Genomics
Mallikarjuna R Pabbidi, Richard J Roman
Previous studies suggest that middle cerebral arteries (MCAs) of Fawn Hooded Hypertensive (FHH) rats exhibit impaired myogenic response and introgression of small region of Brown Norway chromosome 1 containing 15 genes restored the response in FHH.1(BN) congenic rat. The impaired myogenic response in FHH rats is associated with an increase in the activity of the large conductance potassium (BK) channel in vascular smooth muscle cells (VSMCs). The present study examined whether the increased BK channel function in FHH rat alters vasoconstrictor response to serotonin (5-HT)...
October 27, 2016: Physiological Genomics
Christopher A Drummond, Laura E Crotty Alexander, Steven T Haller, Xiaoming Fan, Jeffrey X Xie, David J Kennedy, Jiang Liu, Yanling Yan, Dawn-Alita Hernandez, Denzil P Mathew, Christopher J Cooper, Joseph I Shapiro, Jiang Tian
Clinical studies indicate that smoking combustible cigarettes promotes progression of renal and cardiac injury, leading to functional decline in the setting of chronic kidney disease (CKD). However, basic studies using in vivo small animal models that mimic clinical pathology of CKD are lacking. To address this issue, we evaluated renal and cardiac injury progression and functional changes induced by 4 weeks of daily combustible cigarette smoke exposure in the 5/6(th) partial nephrectomy (PNx) CKD model. Molecular evaluations revealed that cigarette smoke significantly (p<0...
October 27, 2016: Physiological Genomics
Kari Branham, Hiroko Matsui, Pooja Biswas, Aditya A Guru, Michael Hicks, John J Suk, He Li, David Jakubosky, Tao Long, Amalio Telenti, Naoki Nariai, John R Heckenlively, Kelly A Frazer, Paul A Sieving, Radha Ayyagari
While more than 250 genes are known to cause inherited retinal degenerations (IRD), nearly 40-50% of families have the genetic basis for their disease unknown. In this study we sought to identify the underlying cause of inherited retinal degeneration (IRD) in a family by whole genome sequence (WGS) analysis. Clinical characterization including standard ophthalmic examination, fundus photography, visual field testing, electroretinography, and review of medical and family history was performed. WGS was performed on affected and unaffected family members using Illumina HiSeq X10...
October 7, 2016: Physiological Genomics
Jenna F DuMond, Xue Zhang, Yuichiro Izumi, Kevin Ramkissoon, Guanghui Wang, Marjan Gucek, Xujing Wang, Maurice B Burg, Joan D Ferraris
NFAT5 is a transcription factor originally identified because it is activated by hypertonicity and that activation increases expression of genes that protect against the adverse effects of the hypertonicity. However, its targets also include genes not obviously related to tonicity. The transactivating domain of NFAT5 is contained in its c-terminal region, which is predicted to be unstructured. Unstructured regions are common in transcription factors particularly in transactivating domains where they can bind co-regulatory proteins essential to their function...
October 7, 2016: Physiological Genomics
Jeffrey J Widrick, Matthew Alexander, Benjamin Sanchez, Devin Gibbs, Genri Kawahara, Alan Beggs, Louis Kunkel
Sapje zebrafish lack the protein dystrophin and are the smallest vertebrate model of Duchenne muscular dystrophy (DMD). Their small size makes them ideal for large-scale drug discovery screens. However, the extent that sapje mimic the muscle dysfunction of higher vertebrate models of DMD is unclear. We used an optical birefringence assay to differentiate affected dystrophic sapje larvae from their unaffected siblings and then studied trunk muscle contractility at 4-7 days post fertilization. Preparation cross-sectional area (CSA) was similar for affected and unaffected larvae, yet tetanic forces of affected preparations were only 30-60% of normal...
October 7, 2016: Physiological Genomics
Seung Kyum Kim, Joshua J Avila, Michael P Massett
Understanding the genetic influence on vascular reactivity is important for identifying genes underlying impaired vascular function. The purpose of this study was to characterize the genetic contribution to intrinsic vascular function and to identify loci associated with phenotypic variation in vascular reactivity in mice. Concentration response curves to phenylephrine (PE), potassium chloride (KCl), acetylcholine (ACh), and sodium nitroprusside (SNP) were generated in aortic rings from male mice (12-wk old) from 27 inbred mouse strains...
October 7, 2016: Physiological Genomics
Niranjana Natarajan, Daijiro Hori, Sheila Flavahan, Jochen Steppan, Nicholas A Flavahan, Dan E Berkowitz, Jennifer L Pluznick
Short chain fatty acid (SCFA) metabolites are byproducts of gut microbial metabolism that are known to affect host physiology via GPCRs. We previously showed that an acute SCFA bolus decreases blood pressure (BP) in anesthetized mice, an effect mediated via Gpr41. In this study, our aims were to identify the cellular localization of Gpr41 and to determine its role in BP regulation. We localized Gpr41 to the vascular endothelium using RT-PCR: Gpr41 is detected in intact vessels, but is absent from denuded vessels...
September 23, 2016: Physiological Genomics
Yo-Han Kim, Noriyuki Touji, Keiichiro Kizaki, Shiro Kushibiki, Toshihiro Ichijo, Shigeru Sato
We investigated the relationship between ruminal pH and transcriptomic adaptation of the rumen epithelium (RE) of calves fed calf starter with and without forage during the weaning transition. Holstein calves were assigned to groups fed calf starter either with forage (HAY group, n = 3) or without forage (CON group, n = 4). Ruminal pH was measured continuously, and rumen fluid and epithelium were collected 3 weeks after weaning. mRNA expression profiles of the RE were examined by one-color microarray. Differentially expressed genes (DEGs) were investigated using the ingenuity pathway analysis (IPA)...
September 23, 2016: Physiological Genomics
Ryoichi Kawamura, Yasuharu Tabara, Akiko Tsukada, Michiya Igase, Jun Ohashi, Ryo Yamada, Yasunori Takata, Ryuichi Kawamoto, Isao Saito, Hiroshi Onuma, Takeshi Tanigawa, Kazuya Yamada, Norihiro Kato, Yasumasa Ohyagi, Tetsuro Miki, Katsuhiko Kohara, Haruhiko Osawa
Resistin is a cytokine inducing insulin resistance in mice. We previously identified single nucleotide polymorphisms (SNPs) at -420 (rs1862513) and -358 (rs3219175) located in the human resistin gene (RETN) promoter as strong determinants for circulating resistin in the Japanese population. The objective was to identify additional functional variants for circulating resistin. We conducted a genome-wide association study in 448 Japanese subjects. A peak association signal was found on chromosome 19 where RETN is located...
September 23, 2016: Physiological Genomics
Sara M F Turner, Darin J Falk, Barry J Byrne, David D Fuller
Pompe disease, caused by deficiency of acid alpha-glucosidase (GAA), leads to widespread glycogen accumulation and profound neuromuscular impairments. There has been controversy, however, regarding the role of central nervous system pathology in Pompe motor dysfunction. We hypothesized that absence of GAA protein causes progressive activation of neuropathological signaling, including pathways associated with cell death. To test this hypothesis, genomic data (Affymetrix Mouse Gene Array 2.0ST) from the mid-cervical spinal cord in 6- and 16-mo old Pompe (Gaa(-/-)) were evaluated (Broad Institute Molecular Signature Database), along with spinal cord histology...
September 9, 2016: Physiological Genomics
Andreia Pereira, Roberto Palma Dos Reis, Ricardo Rodrigues, Ana Célia Sousa, Susana Gomes, Sofia Borges, Ilidio Ornelas, Ana Isabel Freitas, Graça Guerra, Eva Henriques, Mariana Rodrigues, Sónia Freitas, Carolina Freitas, António Brehm, Décio Pereira, Maria Isabel Mendonça
Recent genetic studies have revealed an association between polymorphisms at the ADAMTS7 gene locus and coronary artery disease (CAD) risk. Functional studies have shown that a CAD-associated polymorphism (rs3825807) affects ADAMTS7 maturation and VSMC migration. Here, we tested whether ADAMTS7 (A/G) SNP is associated with cardiovascular (CV) survival in patients with established CAD. A cohort of 1128 patients with angiographic proven CAD, who were followed-up prospectively for a mean follow-up of 63 (range 6 -182) months, were genotyped for rs3825807 A/G...
September 9, 2016: Physiological Genomics
Ingrid Eftedal, Arnar Flatberg, Ivan Drvis, Zeljko Dujic
Freedivers hold their breath while diving, causing blood oxygen levels to decrease (hypoxia) while carbon dioxide increases (hypercapnia). Whereas blood gas changes are presumably involved in the progression of respiratory diseases, less is known about their effect on healthy individuals. Here we have used gene expression profiling to analyze elite athletes' immune and inflammatory responses to freediving. Blood was collected before, 1 and 3 h after a series of maximal dynamic and static apneas in a pool, and peripheral blood gene expression was mapped on genome-wide microarrays...
September 9, 2016: Physiological Genomics
Aoy Tomita-Mitchell, Karl D Stamm, Donna K Mahnke, Min-Su Kim, Pip M Hidestrand, Huan Ling Liang, Mary A Goetsch, Mats Hidestrand, Pippa Simpson, Andrew N Pelech, James S Tweddell, D Woodrow Benson, John W Lough, Michael E Mitchell
Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease (CHD). Although prior studies suggest that HLHS has a complex genetic inheritance, its etiology remains largely unknown. The goal of this study was to characterize a risk gene in HLHS and its effect on HLHS etiology and outcome. We performed next-generation sequencing on a multigenerational family with a high prevalence of CHD/HLHS, identifying a rare variant in the α-myosin heavy chain (MYH6) gene...
December 1, 2016: Physiological Genomics
Aksone Nouvong, Aaron M Ambrus, Ellen R Zhang, Lucas Hultman, Hilary A Coller
Chronic wounds are a common and debilitating complication for the diabetic population. It is challenging to study the development of chronic wounds in human patients; by the time it is clear that a wound is chronic, the early phases of wound healing have passed and can no longer be studied. Because of this limitation, mouse models have been employed to better understand the early phases of chronic wound formation. In the past few years, a series of reports have highlighted the importance of reactive oxygen species and bacterial biofilms in the development of chronic wounds in diabetics...
December 1, 2016: Physiological Genomics
Ryan D Sheldon, Kayla M Kanosky, Kevin D Wells, Lili Miles, James W Perfield, Stavra Xanthakos, Thomas H Inge, R Scott Rector
Mechanisms responsible for progression of nonalcoholic fatty liver disease (NAFLD) to steatohepatitis (NASH) remain poorly defined. To examine the potential contribution of adipose tissue to NAFLD progression, we performed a complete transcriptomic analysis using RNA sequencing (RNA-Seq) on intra-abdominal adipose tissue (IAT) from severely obese adolescents [Mage 16.9 ± 0.4 yr, body mass index (BMI) z-score 2.7 ± 0.1] undergoing bariatric surgery and liver biopsy categorized into three groups: no steatosis (normal, n = 8), steatosis only (n = 13), or NASH (n = 10) by liver histology...
December 1, 2016: Physiological Genomics
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