Browsing by Subject "nervous system"
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Item Bone Morphogenetic Protein 4 inhibits TGF-beta2 Stimulation of Extracellular Matrix Proteins in Optic Nerve Head Cells: Role of Gremlin in ECM Modulation(2005-05-01) Zode, Gulab S.; Wordinger, Robert J.Zode, Gulab Shalikram, Bone Morphogenetic Protein 4 Inhibits TGF-β2 Stimulation of Extracellular Matrix Proteins in Optic Nerve Head Cells: Role of Gremlin in ECM Modulation . Doctor of Philosophy (Cell Biology and Genetics), May 2008; 177pp; 34 figures; bibliography, 192 titles. The glaucomatous neuropathy is caused by irreversible loss of retinal ganglion axons in the optic nerve head (ONH). The extensive remodeling of the extracellular matrix (ECM) in the glaucomatous ONH including increased synthesis and deposition of ECM (increased collagens, basement proteins, and elastin) is associated with loss of axons. Transforming growth factor-beta2 (TGF-β2) is increased in glaucomatous ONH and is thought to be responsible for increased synthesis and deposition of ECM proteins of the ONH. Bone morphogenetic proteins (BMPs) normally maintain the balance of ECM proteins via opposing TGF-β2 stimulated ECM proteins in various cell types. BMP antagonist gremlin inhibits BMPs function, thus may plan an important role in ECM modulation. We previously demonstrated that human ONH expresses BMP-4, BMP receptor and BMP antagonist gremlin. Therefore, we hypothesize that elevated TGF-β2 in the glaucomatous ONH induces gremlin expression that blocks BMP-4 inhibition of TGF-β2 signaling, leading to increased ECM synthesis and deposition. First, we examined whether human ONH tissues and ONH cells express the canonical BMP signaling pathway. This study demonstrated that ONH tissues and ONH cells express BMP-4 and Smad signaling pathway. Treatment of ONH cells with BMP-4 increased phosphorylation of R-Smad/1/58/ phosphorylation and interaction with Co-Smad4 indicating activation of the Smad signaling pathway. Therefore, cells within the human ONH can respond to locally released BMP via activation of Smad signaling. Second, we examined the signaling pathways utilized by TGF-β2 to stimulate ECM in ONH cells. This study demonstrated that TGF-β2 is increased in glaucomatous ONH. Recombinant TGF-β2 increased ECM deposition in ONH cells. TGF-β2 activated phosphorylation of R-smad2/3 but did not alter phosphorylation of ERK1/2, p38, and JNK1/2 in ONH cells. Inhibition of either TGF-β I receptor activity or phosphorylation of R-Smad3 or knockdown of R-Smad2/3 via siRNA reduced TGF-β2 stimulated ECM in ONH cells. Thus, TGF-β2 requires R-Smad2/3 to stimulate ECM proteins in ONH cells. Lastly, we investigated the potential effects of BMP-4 and gremlin on TGF-β2 stimulated ECM in ONH cells. BMP-4 significantly reduced TGF-β2 stimulation of ECM proteins. Addition of gremlin blocked the BMP-4 effect, increasing ECM proteins in ONH cells. Gremlin levels were significantly increased in the human glaucomatous ONH tissues. Interestingly, recombinant gremlin also increased ECM proteins in ONH cells. Gremlin stimulation of ECM proteins required activation of the TGF-β receptor and R-Smad3. TGF-β2 increased gremlin mRNA and protein in ONH cells. Thus, TGF-β2 induced gremlin expression intensifies TGF-β2 effects on ECM metabolism by inhibiting BMP-4 antagonism of TGF-β2 signaling. In conclusion, elevated TGF-β2 and gremlin in the glaucomatous ONH are involved in the pathogenesis of glaucomatous ONH. Elevated TGF-β2 directly increases ECM and also induces gremlin expression, which further aids TGF-β2 to stimulate ECM via inhibiting BMPs antagonism of TGF-β2 signaling, leading to unopposed TGF-β2 stimulated ECM proteins. Interestingly, R-smad3 is required for TGF-β2 or gremlin induced ECM remodeling in ONH cells. Therefore, modulation of R-smad3 provides a novel therapeutic target for preventing ECM remodeling in glaucoma.Item Lectures on Conditioned Reflexes Twenty-five Years of Objective Study of the Higher Nervous Activity (Behaviour) of Animals(International Publishers, 1928-01-01) Gantt, W.; Volborth, G.; Cannon, Walter; Pavlov, IvanTranslator's Preface 9 I. P. Pavlov: A Biographical Sketch, By Dr. W. Horsley Gantt . 11 Introduction To The English Translation, By Prof. Walter B. Cannon 33 Author's Preface To The English Translation 35 Preface To The First Russian Edition • 37 Chapter. I. Experimental Psychology And Psycho-Pathology In Animals – 47 II. . The Psychical Secretion Of The Salivary Glands (Complex Nervous Phenomena In The Work Of The Salivary Glands) 61 III. The First Sure Steps Along The Path Of A New Investigation 76 IV. Scientific Study Of The So-Called Psychical Processes In The Higher Animals 81 V. Conditioned Reflexes In Dogs After Destruction Of Different Parts Of The Cerebral Hemispheres 97 VI. The Cortical Taste Centre Of Dr. Gorshkov 99 VII. Mechanism Of The Highest Parts Of The Central Nervous System As Shown From The Study Of The Conditioned Reflexes 100 VIII. Further Advances Of The Objective Analysis Of Complex Nervous Phenomena, And Its Comparison With The IX. Subjective Conception Of These Phenomena • 103 X. Some General Facts About The Cerebral Centres , 115 XI. Natural Science And The Brain 120 XII. The Task And The Arrangement Of A Laboratory For The Study Of The Normal Activity Of The Highest Parts Of The Central Nervous System In The Higher Animals • 131 XIII. A Laboratory For The Study Of The Activity Of The Central Nervous System In The Higher Animals 144 XIV. The Food Centre • 147 XV. Some Fundamental Laws Of The Work Of The Cerebral Hemispheres 156 XVI. Destruction Of The Skin Analyser 165 XVII. The Process Of Differentiation Of Stimulations In The Hemispheres Of The Brain 170 XVIII. Some Principles Of The Activity Of The Central Nervous System As Shown From The Study Of Conditioned Reflexes ; Interaction Of Centres 182 XIX. Summary Of Results Of Removal Of Different Parts Of The Cerebral Hemispheres 193 XX. Internal Inhibition As A Function Of The Cerebral Hemispheres 205 XXI. The Objective Study Of The Highest Nervous Activity Of Animals . 213 XXII. The Study Of The Highest Nervous Activity • 223 XXIII. The Instability (Lability) Of Internal Inhibition In Conditioned Reflexes . 238 XXIV. The Pure Physiology Of The Brain 241 XXV. Some Facts About The Physiology Of Sleep 250 XXVI. An Analysis Of Some Complex Reflexes In The Dog; And The Relative Strength And Tension Of Several Centres 255 XXVII. Physiology And Psychology In The Study Of The Higher Nervous Activity Of Animals 261 XXVIII. The Reflex Of Purpose 275 XXIX. The Reflex Of Freedom 282 XXX. How Psychiatry May Help Us To Understand The Physiology Of The Cerebral Hemispheres 287 XXXI. Hypnotism In Animals 294 XXXII. The Normal Activity And General Constitution Of The Cerebral Hemispheres . 296 XXXIII. Internal Inhibition And Sleep-One And The Same Process 305 XXXIV. Changes In The Excitability Of Various Points Of The Cerebral Cortex As One Of Its Functional Characteristics 319 XXXV. Another Problem In Cerebral Physiology 326 XXXVI. The Latest Successes Of The Objective Study Of The Highest Nervous Activity 329 XXXVII. Relation Between Excitation And Inhibition And Their Delimitations; Experimental Neuroses In Dogs 339 XXXVIII. Effect Of Interrupting The Experimentation In Dogs With Conditioned Reflexes 350 XXXIX. Normal And Pathological States Of The Hemispheres 353 XL. The Inhibitory Type Of Nervous Systems In The Dog 363 XLI. A Physiological Study Of The Types Of Nervous Systems, I.E., Of Temperaments • 370 XLII. Certain Problems In The Physiology Of The Cerebral Hemispheres 379 Bibliography • 395 Index To Names 409 Index To .Subjects 410