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The Gain-of-Function Integrin β3 Pro33 Variant Alters the Serotonin System in the Mouse Brain.
Dohn MR, Kooker CG, Bastarache L, Jessen T, Rinaldi C, Varney S, Mazalouskas MD, Pan H, Oliver KH, Velez Edwards DR, Sutcliffe JS, Denny JC, Carneiro AMD
(2017) J Neurosci 37: 11271-11284
MeSH Terms: Animals, Brain, Female, Gain of Function Mutation, Gene Knock-In Techniques, Genetic Variation, Humans, Integrin beta3, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Proline, Protein Binding, Serotonin, Serotonin Plasma Membrane Transport Proteins
Show Abstract · Added November 2, 2017
Engagement of integrins by the extracellular matrix initiates signaling cascades that drive a variety of cellular functions, including neuronal migration and axonal pathfinding in the brain. Multiple lines of evidence link the gene encoding the integrin β3 subunit with the serotonin (5-HT) system, likely via its modulation of the 5-HT transporter (SERT). The coding polymorphism Leu33Pro (rs5918, Pl) produces hyperactive αvβ3 receptors that influence whole-blood 5-HT levels and may influence the risk for autism spectrum disorder (ASD). Using a phenome-wide scan of psychiatric diagnoses, we found significant, male-specific associations between the Pro33 allele and attention-deficit hyperactivity disorder and ASDs. Here, we used knock-in (KI) mice expressing an variant that phenocopies the human Pro33 variant to elucidate the consequences of constitutively enhanced αvβ3 signaling to the 5-HT system in the brain. KI mice displayed deficits in multiple behaviors, including anxiety, repetitive, and social behaviors. Anatomical studies revealed a significant decrease in 5-HT synapses in the midbrain, accompanied by decreases in SERT activity and reduced localization of SERTs to integrin adhesion complexes in synapses of KI mice. Inhibition of focal adhesion kinase (FAK) rescued SERT function in synapses of KI mice, demonstrating that constitutive active FAK signaling downstream of the Pro32Pro33 integrin αvβ3 suppresses SERT activity. Our studies identify a complex regulation of 5-HT homeostasis and behaviors by integrin αvβ3, revealing an important role for integrins in modulating risk for neuropsychiatric disorders. The integrin β3 Leu33Pro coding polymorphism has been associated with autism spectrum disorders (ASDs) within a subgroup of patients with elevated blood 5-HT levels, linking integrin β3, 5-HT, and ASD risk. We capitalized on these interactions to demonstrate that the Pro33 coding variation in the murine integrin β3 recapitulates the sex-dependent neurochemical and behavioral attributes of ASD. Using state-of-the-art techniques, we show that presynaptic 5-HT function is altered in these mice, and that the localization of 5-HT transporters to specific compartments within the synapse, disrupted by the integrin β3 Pro33 mutation, is critical for appropriate reuptake of 5-HT. Our studies provide fundamental insight into the genetic network regulating 5-HT neurotransmission in the CNS that is also associated with ASD risk.
Copyright © 2017 the authors 0270-6474/17/3711272-14$15.00/0.
2 Communities
3 Members
0 Resources
16 MeSH Terms
Proline Precursors and Collagen Synthesis: Biochemical Challenges of Nutrient Supplementation and Wound Healing.
Albaugh VL, Mukherjee K, Barbul A
(2017) J Nutr 147: 2011-2017
MeSH Terms: Amino Acids, Animals, Collagen, Dietary Supplements, Disease Models, Animal, Humans, Proline, Wound Healing
Show Abstract · Added January 4, 2019
Wound healing is a complex process marked by highly coordinated immune fluxes into an area of tissue injury; these are required for re-establishment of normal tissue integrity. Along with this cascade of cellular players, wound healing also requires coordinated flux through a number of biochemical pathways, leading to synthesis of collagen and recycling or removal of damaged tissues. The availability of nutrients, especially amino acids, is critical for wound healing, and enteral supplementation has been intensely studied as a potential mechanism to augment wound healing-either by increasing tensile strength, decreasing healing time, or both. From a practical standpoint, although enteral nutrient supplementation may seem like a reasonable strategy to augment healing, a number of biochemical and physiologic barriers exist that limit this strategy. In this critical review, the physiology of enteral amino acid metabolism and supplementation and challenges therein are discussed in the context of splanchnic physiology and biochemistry. Additionally, a review of studies examining various methods of amino acid supplementation and the associated effects on wound outcomes are discussed.
© 2017 American Society for Nutrition.
0 Communities
1 Members
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MeSH Terms
Loss of SPRR3 in ApoE-/- mice leads to atheroma vulnerability through Akt dependent and independent effects in VSMCs.
Lietman CD, Segedy AK, Li B, Fazio S, Atkinson JB, Linton MF, Young PP
(2017) PLoS One 12: e0184620
MeSH Terms: Animals, Apolipoproteins E, Cornified Envelope Proline-Rich Proteins, Female, Fibronectins, Immunoblotting, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Real-Time Polymerase Chain Reaction, Signal Transduction
Show Abstract · Added April 10, 2018
Vascular smooth muscle cells (VSMCs) represent important modulators of plaque stability in advanced lesions. We previously reported that loss of small proline-rich repeat protein 3 (Sprr3), leads to VSMC apoptosis in a PI3K/Akt-dependent manner and accelerates lesion progression. Here, we investigated the role of Sprr3 in modulating plaque stability in hyperlipidemic ApoE-/- mice. We show that loss of Sprr3 increased necrotic core size and reduced cap collagen content of atheromas in brachiocephalic arteries with evidence of plaque rupture and development of intraluminal thrombi. Moreover, Sprr3-/-ApoE-/- mice developed advanced coronary artery lesions accompanied by intraplaque hemorrhage and left ventricle microinfarcts. SPRR3 is known to reduce VSMC survival in lesions by promoting their apoptosis. In addition, we demonstrated that Sprr3-/- VSMCs displayed reduced expression of procollagen in a PI3K/Akt dependent manner. SPRR3 loss also increased MMP gelatinase activity in lesions, and increased MMP2 expression, migration and contraction of VSMCs independently of PI3K/Akt. Consequently, Sprr3 represents the first described VSMC modulator of each of the critical features of cap stability, including VSMC numbers, collagen type I synthesis, and protease activity through Akt dependent and independent pathways.
0 Communities
1 Members
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MeSH Terms
Hypoxia-inducible factor prolyl-4-hydroxylation in FOXD1 lineage cells is essential for normal kidney development.
Kobayashi H, Liu J, Urrutia AA, Burmakin M, Ishii K, Rajan M, Davidoff O, Saifudeen Z, Haase VH
(2017) Kidney Int 92: 1370-1383
MeSH Terms: Anemia, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Hypoxia, Clinical Trials, Phase III as Topic, Disease Models, Animal, Enzyme Inhibitors, Forkhead Transcription Factors, Humans, Hydroxylation, Hypoxia-Inducible Factor-Proline Dioxygenases, Kidney, Kidney Diseases, Mice, Molecular Targeted Therapy, Mutation, Organ Size, Procollagen-Proline Dioxygenase, Renal Insufficiency, Stromal Cells
Show Abstract · Added November 21, 2017
Hypoxia in the embryo is a frequent cause of intra-uterine growth retardation, low birth weight, and multiple organ defects. In the kidney, this can lead to low nephron endowment, predisposing to chronic kidney disease and arterial hypertension. A key component in cellular adaptation to hypoxia is the hypoxia-inducible factor pathway, which is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2, and PHD3. In the adult kidney, PHD oxygen sensors are differentially expressed in a cell type-dependent manner and control the production of erythropoietin in interstitial cells. However, the role of interstitial cell PHDs in renal development has not been examined. Here we used a genetic approach in mice to interrogate PHD function in FOXD1-expressing stroma during nephrogenesis. We demonstrate that PHD2 and PHD3 are essential for normal kidney development as the combined inactivation of stromal PHD2 and PHD3 resulted in renal failure that was associated with reduced kidney size, decreased numbers of glomeruli, and abnormal postnatal nephron formation. In contrast, nephrogenesis was normal in animals with individual PHD inactivation. We furthermore demonstrate that the defect in nephron formation in PHD2/PHD3 double mutants required intact hypoxia-inducible factor-2 signaling and was dependent on the extent of stromal hypoxia-inducible factor activation. Thus, hypoxia-inducible factor prolyl-4-hydroxylation in renal interstitial cells is critical for normal nephron formation.
Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
20 MeSH Terms
Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus.
Karimy JK, Zhang J, Kurland DB, Theriault BC, Duran D, Stokum JA, Furey CG, Zhou X, Mansuri MS, Montejo J, Vera A, DiLuna ML, Delpire E, Alper SL, Gunel M, Gerzanich V, Medzhitov R, Simard JM, Kahle KT
(2017) Nat Med 23: 997-1003
MeSH Terms: Acetazolamide, Animals, Antioxidants, Blotting, Western, Bumetanide, Cerebral Hemorrhage, Cerebral Ventricles, Cerebrospinal Fluid, Choroid Plexus, Diuretics, Gene Knockdown Techniques, Gene Knockout Techniques, Hydrocephalus, Immunoblotting, Immunohistochemistry, Immunoprecipitation, Inflammation, NF-kappa B, Proline, Protein-Serine-Threonine Kinases, Rats, Rats, Wistar, Salicylanilides, Solute Carrier Family 12, Member 2, Sulfonamides, Thiocarbamates, Toll-Like Receptor 4
Show Abstract · Added April 3, 2018
The choroid plexus epithelium (CPE) secretes higher volumes of fluid (cerebrospinal fluid, CSF) than any other epithelium and simultaneously functions as the blood-CSF barrier to gate immune cell entry into the central nervous system. Posthemorrhagic hydrocephalus (PHH), an expansion of the cerebral ventricles due to CSF accumulation following intraventricular hemorrhage (IVH), is a common disease usually treated by suboptimal CSF shunting techniques. PHH is classically attributed to primary impairments in CSF reabsorption, but little experimental evidence supports this concept. In contrast, the potential contribution of CSF secretion to PHH has received little attention. In a rat model of PHH, we demonstrate that IVH causes a Toll-like receptor 4 (TLR4)- and NF-κB-dependent inflammatory response in the CPE that is associated with a ∼3-fold increase in bumetanide-sensitive CSF secretion. IVH-induced hypersecretion of CSF is mediated by TLR4-dependent activation of the Ste20-type stress kinase SPAK, which binds, phosphorylates, and stimulates the NKCC1 co-transporter at the CPE apical membrane. Genetic depletion of TLR4 or SPAK normalizes hyperactive CSF secretion rates and reduces PHH symptoms, as does treatment with drugs that antagonize TLR4-NF-κB signaling or the SPAK-NKCC1 co-transporter complex. These data uncover a previously unrecognized contribution of CSF hypersecretion to the pathogenesis of PHH, demonstrate a new role for TLRs in regulation of the internal brain milieu, and identify a kinase-regulated mechanism of CSF secretion that could be targeted by repurposed US Food and Drug Administration (FDA)-approved drugs to treat hydrocephalus.
0 Communities
1 Members
0 Resources
MeSH Terms
Oxygen sensors as therapeutic targets in kidney disease.
Haase VH
(2017) Nephrol Ther 13 Suppl 1: S29-S34
MeSH Terms: Erythropoietin, Homeostasis, Humans, Hypoxia, Hypoxia-Inducible Factor-Proline Dioxygenases, Kidney, Oxygen, Prolyl-Hydroxylase Inhibitors, Renal Insufficiency, Chronic
Show Abstract · Added June 7, 2017
Hypoxia is a common clinical problem that has profound effects on renal homeostasis. Prolyl-4-hydroxylases PHD1, 2 and 3 function as oxygen sensors and control the activity of hypoxia-inducible factor (HIF), an oxygen-sensitive transcription factor that regulates a multitude of hypoxia responses, which help cells and tissues to adapt to low oxygen environments. This review provides an overview of the molecular mechanisms that govern these hypoxia responses and discusses clinical experience with compounds that inhibit prolyl-4-hydroxylases to harness HIF responses for therapy in nephrology.
Copyright © 2017 Société francophone de néphrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.
0 Communities
1 Members
0 Resources
9 MeSH Terms
Therapeutic targeting of the HIF oxygen-sensing pathway: Lessons learned from clinical studies.
Haase VH
(2017) Exp Cell Res 356: 160-165
MeSH Terms: Anemia, Animals, Erythropoiesis, Humans, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases, Oxygen
Show Abstract · Added May 10, 2017
The oxygen-sensitive hypoxia-inducible factor (HIF) pathway plays a central role in the control of erythropoiesis and iron metabolism. The discovery of prolyl hydroxylase domain (PHD) proteins as key regulators of HIF activity has led to the development of inhibitory compounds that are now in phase 3 clinical development for the treatment of renal anemia, a condition that is commonly found in patients with advanced chronic kidney disease. This review provides a concise overview of clinical effects associated with pharmacologic PHD inhibition and was written in memory of Professor Lorenz Poellinger.
Copyright © 2017 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
8 MeSH Terms
HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism.
Haase VH
(2017) Hemodial Int 21 Suppl 1: S110-S124
MeSH Terms: Anemia, Barbiturates, Clinical Trials as Topic, Erythropoiesis, Erythropoietin, Glycine, Humans, Hypoxia-Inducible Factor-Proline Dioxygenases, Iron, Isoquinolines, Picolinic Acids, Prolyl-Hydroxylase Inhibitors, Renal Dialysis
Show Abstract · Added April 28, 2017
A classic response to systemic hypoxia is the increase in red blood cell production. This response is controlled by the prolyl hydroxylase domain/hypoxia-inducible factor (HIF) pathway, which regulates a broad spectrum of cellular functions. The discovery of this pathway as a key regulator of erythropoiesis has led to the development of small molecules that stimulate the production of endogenous erythropoietin and enhance iron metabolism. This review provides a concise overview of the cellular and molecular mechanisms that govern HIF-induced erythropoietic responses and provides an update on clinical experience with compounds that target HIF-prolyl hydroxylases for anemia therapy.
© 2017 International Society for Hemodialysis.
0 Communities
1 Members
0 Resources
13 MeSH Terms
Local Delivery of PHD2 siRNA from ROS-Degradable Scaffolds to Promote Diabetic Wound Healing.
Martin JR, Nelson CE, Gupta MK, Yu F, Sarett SM, Hocking KM, Pollins AC, Nanney LB, Davidson JM, Guelcher SA, Duvall CL
(2016) Adv Healthc Mater 5: 2751-2757
MeSH Terms: Animals, Cell Proliferation, Diabetes Mellitus, Male, Neovascularization, Physiologic, Procollagen-Proline Dioxygenase, RNA, Small Interfering, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species, Tissue Engineering, Tissue Scaffolds, Wound Healing
Show Abstract · Added March 14, 2018
Small interfering RNA (siRNA) delivered from reactive oxygen species-degradable tissue engineering scaffolds promotes diabetic wound healing in rats. Porous poly(thioketal-urethane) scaffolds implanted in diabetic wounds locally deliver siRNA that inhibits the expression of prolyl hydroxylase domain protein 2, thereby increasing the expression of progrowth genes and increasing vasculature, proliferating cells, and tissue development in diabetic wounds.
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
0 Communities
2 Members
0 Resources
13 MeSH Terms
Prolyl-4-hydroxylase 2 and 3 coregulate murine erythropoietin in brain pericytes.
Urrutia AA, Afzal A, Nelson J, Davidoff O, Gross KW, Haase VH
(2016) Blood 128: 2550-2560
MeSH Terms: Animals, Brain, Erythropoietin, Gene Expression Regulation, Hypoxia, Brain, Hypoxia-Inducible Factor-Proline Dioxygenases, Mice, Mice, Transgenic, Pericytes, Procollagen-Proline Dioxygenase, Transcription Factors, Transcription, Genetic
Show Abstract · Added September 30, 2016
A classic response to systemic hypoxia is the increased production of red blood cells due to hypoxia-inducible factor (HIF)-mediated induction of erythropoietin (EPO). EPO is a glycoprotein hormone that is essential for normal erythropoiesis and is predominantly synthesized by peritubular renal interstitial fibroblast-like cells, which express cellular markers characteristic of neuronal cells and pericytes. To investigate whether the ability to synthesize EPO is a general functional feature of pericytes, we used conditional gene targeting to examine the von Hippel-Lindau/prolyl-4-hydroxylase domain (PHD)/HIF axis in cell-expressing neural glial antigen 2, a known molecular marker of pericytes in multiple organs. We found that pericytes in the brain synthesized EPO in mice with genetic HIF activation and were capable of responding to systemic hypoxia with the induction of Epo. Using high-resolution multiplex in situ hybridization, we determined that brain pericytes represent an important cellular source of Epo in the hypoxic brain (up to 70% of all Epo-expressing cells). We furthermore determined that Epo transcription in brain pericytes was HIF-2 dependent and cocontrolled by PHD2 and PHD3, oxygen- and 2-oxoglutarate-dependent prolyl-4-hydroxylases that regulate HIF activity. In summary, our studies provide experimental evidence that pericytes in the brain have the ability to function as oxygen sensors and respond to hypoxia with EPO synthesis. Our findings furthermore suggest that the ability to synthesize EPO may represent a functional feature of pericytes in the brain and kidney.
0 Communities
1 Members
0 Resources
12 MeSH Terms