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Studium role konformace N-konce řetězce B insulinu ve vazbě na insulinový receptor / Study of the role of the B-chain N-terminus conformation of insulin in binding to the insulin receptorKosinová, Lucie January 2013 (has links)
According to the International Diabetes Federation (IDF), there were 371 million people in the age from 20 to 79 years worldwide affected by diabetes in 2012. This means diabetes has become a global epidemic disease and, therefore, the importace of insulin research still grows. Insulin is a protein hormone that plays a key role in regulating blood glucose level which has a widespread impact on whole metabolism. Insulin acts through binding of its monomeric form to the insulin receptor. It is clear that insulin monomer has to undergo structural changes upon binding to the insulin receptor as the residues which are crucial for the interaction are burried within the native form. According to studies of highly active hormone analogs and the new information about the insulin-insulin receptor complex, there is a strong evidence that the C-terminal part of the B-chain is a dynamic element in insulin activation and receptor binding. Probably, there is also a great importance of the B-chain N- terminus and the transition between T and R conformations of insulin. However, the exact significance of the T and R states of insulin still remains unclear. In this work, several new insulin analogs AibB3-insulin, AibB5-insulin, AibB8- insulin, N-MeAlaB8-insulin and D-ProB8-insulin were prepared for the purpose of...
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Příprava a charakterizace selektivních analogů insulinu a IGF-2 pro různé isoformy insulinového receptoru / Preparation and characterization of selective analogues of insulin and IGF-II for various isoforms of the insulin receptorKřížková, Květoslava January 2014 (has links)
Modern lifestyle with its lack of exercise and healthy diet often leads to obesity which is accompanied by a decreasing biological effect of insulin and the onset of hyperinsulinemia, and consequently type 2 diabetes. Persistently high levels of insulin stimulate signalling pathways with growth effects; cells thus become more sensitive to mitogenic effects of all growth factors which may even lead to the loss of control over cell proliferation and the rise of various malignancies. Due to a high degree of structure homology of insulin, IGF-I/II as well as particular IR (existing in "mitogenic" IR-A isoform and "metabolic" IR-B isoform) and IGF-1R, there are a number of cross- interaction among hormones and receptors; nevertheless, the biological response may be different during the binding to a receptor. The determination of the crucial structural regions in insulin and IGF which are responsible for binding to the receptors could lead to the evolution of selective insulin analogues with strengthen metabolic effects, or could lead to the evolution of selective antagonism of IGF which would, in turn, suppress the mitogenic effect. The highest overlap is between insulin and IGF-II since both hormones are able to bind to the isoform A of an insulin receptor (IR-A) with a high affinity, and to activate...
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Insulin Receptor Substrate-2 (IRS-2): A Novel Hypoxia-Responsive Gene in Breast Cancer: A DissertationMardilovich, Katerina 11 May 2011 (has links)
Breast cancer is the most common malignancy among women in the U.S. While many successful treatments exist for primary breast cancer, very few are available for patients with metastatic disease. The purpose of this study was to understand the role of Insulin Receptor Subtrate-2 (IRS-2) in breast cancer metastasis. IRS-2 belongs to the IRS family of cytoplasmic adaptor proteins that mediate signaling from cell surface receptors, many of which have been implicated in cancer. Although the IRS proteins are highly homologous in structure and have some complementary functions, growing evidence supports that the IRS proteins have unique roles in cancer. IRS-1 has been shown to promote tumor cell proliferation, while IRS-2 has been positively associated with cancer cell invasion, glycolysis and tumor metastasis. In the current work, we identified IRS-2 as a novel hypoxia-responsive gene in breast carcinoma cells. In contrast, IRS-1 expression does not increase in response to hypoxia, supporting the notion of their non-overlapping functions. Hypoxia promotes the adaptation and resistance of cancer cells to chemo- and radiation therapy, and also promotes tumor cell survival, invasion and metastasis by selecting for aggressive tumor cells that can survive under stressful low oxygen conditions. We have shown that IRS-2 upregulation in response to hypoxia promotes Akt signaling and tumor cell viability and invasion. We identified a cell context-dependent role for Hypoxia Inducible Factor (HIF) in the regulation of IRS-2 expression in hypoxia, with HIF-2 playing a more dominant role than HIF-1. We also demonstrate that binding of Snail, a regulator of the EMT, to the IRS-2 promoter keeps the chromatin in an open conformation that is permissive for HIF-dependent transcription of IRS-2 in hypoxia. IRS-2 is not upregulated by hypoxia in well-differentiated epithelial-like carcinoma cells that do not express Snail, implicating IRS-2 gene expression as part of the EMT programming. In summary, we have identified an endogenous mechanism by which cancer cells can shift the balance of IRS-1 and IRS-2 to favor IRS-2 expression and function, which promotes survival, invasion, and ultimately metastasis. Understanding the mechanism of IRS-2 regulation by hypoxia may reveal new therapeutic targets for metastatic breast cancer.
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Uloga insulinskih i IGF1 receptora u regulaciji steroidogeneze i mitohondrijallne biogenze u Leydigovim ćelijama / The role of insulin and IGF1 receptors in regulation of teroidogenesis and mitochondrial biogenesis in Leydig cellsRadović Sava 31 May 2019 (has links)
<p>Leydig-ove ćelije testisa su primarno mesto sinteze muških polnih hormona. Ovi hormoni su neophodani za reproduktivno, ali i za opšte zdravlje budući da su<br />ozbiljni zdravstveni problemi često povezani sa njihovom smanjenom produkcijom. Insulin i insulinu sličan faktor rasta 1, IGF1 <em>(engl.</em> insulin like growth factor 1), i<br />signalizacija koju pokreću preko svojih receptora (INSR i IGF1R), su jedan od ključnih faktora koji regulišu specifični razvoj tkiva, pa i samih gonada. Ipak, uloga i<br />mehanizmi delovanja ovih receptora u steroidogenim tkivima nisu u potpunosti poznati. Stoga je istraživanje uokviru ove doktorske disertacije koncipirano sa ciljem da se, na modelu prepubertalnih (P21) i adultnih (P80) mužjaka miševa sa kondicionalnom delecijom<em> Insr </em>i <em>Igf1</em>r gena u steroidogenim ćelijama (Insr/Igf1r-DKO), definiše uloga INSR i IGF1R u regulisanju diferencijacije i steroidogene funkcije Leydig-ovih ćelija. Pored toga, mužjaci i ženke P21 miševa sa istom delecijom su korišćeni za praćenje ekspresije glavnih markera mitohondrijalne biogeneze i fuzije/arhitekture u Leydigovim ćelijama, ovarijumima i nadbubrežnim žlezdama. Rezultati su potvrdili da delecija Insr i Igf1r u<br />steroidogenim tkivima utiče na diferencijaciju i funkcionalne karakteristike Leydig-ovih ćelija P21 i P80 miševa, upućujući na pojavu tzv. „feminizacije“. Broj<br />Leydig-ovih ćelija izolovanih iz P21 i P80 Insr/Igf1rDKO miševa bio je smanjen, a morfologija i ultrastruktura ovih ćelija izmenjene kod P21 Insr/Igf1rDKO miševa. Steroidogeni kapacitet i aktivnost, kao i ekspresija glavnih elemenata steroidogene mašinerije <em>(Lhcgr, Star, Cyp11a1, Cyp17a1, Hsd3b1 i 6, Hsd17b3,</em><br /><em>Sf</em>1) bili su smanjeni u Leydig-ovim ćelijama P21 i P80 <em>Insr/Igf1</em>r-DKO miševa, dok je ekspresija transkripcionih represora steroidogeneze (Arr19 i Dax1) bila povećana specifično u istim ćelijama, ali ne i u ostatku testisa.<br />Transkripcioni profil markera muškog pola (<em>Sry, Sox9, Amh</em>) bio je izmenjen u Leydig-ovim ćelijama P21 i P80 <em>Insr/Igf1r</em>-DKO miševa. Transkripcija markera ženskog pola (<em>Rspo1, Wnt4</em>) u testisima, kao i ekspresija Cyp19a1 i produkcija estradiola (E2) u Leydig-ovim ćelijama, P21 i P80 <em> Insr/Igf1r</em>-DKO miševa bile su povećane. Transkripcija markera mitohondrijalne biogenze (<em>Ppargc1a, Tfam</em>, <em>Mtnd1</em>) bila je smanjena u Leydigovim ćelijama P21 <em>Insr/Igf1r</em>-DKO miševa, dok supromene ekspresije izostale u ovarijumima ženki istog genotipa. Isti markeri su bili povećani u nabdubrežnim žlezdama oba pola. Markeri mitohondrijalne fuzije/arhitekture (<em>Mfn1 i Mfn2)</em> bili su povećani u Leydig-ovim ćelijama P21 <em>Insr/Igf1r</em>-DKO miševa, što je praćeno i narušenom mitohondrijalnom fazom steroidogeneze (produkcija progesterona), kao i brojem i morfologijom ovim organela. Ekspresija istih markera u ovarijumima bila je nepromenjena. Sumirano, rezultati ovog istraživanja su pokazali da su INSR i IGF1R važni za diferencijaciju i steroidogenu funkciju Leydig-ovih ćelija P21 i P80 miševa. Takođe, ovi receptori su važni regulatori markera mitohondrijalne biogeneze i fuzije/arhiteture u steroidogenim ćelijama muških gonada P21 miševa, ali ne i u steroidogenim ćelijama ovarijuma. </p> / <p>Leydig cells of testes are the primary site of the male sex hormones synthesis. These hormones are indispensable for both reproductive and general health since serious health problems are often associated with their reduced production. Insulin and insulin-like growth factor 1, IGF1 (insulin like growth factor 1), and signaling triggered through their receptors (INSR and IGF1R), are one of the key factors that regulate specific development of tissue including gonads. However, the role and mechanisms of these receptors action in steroidogenic tissues are not known enough. This study was designed to observe the role of INSR and IGF1R in regulating the differentiation and steroidogenic function of Leydig cells by using the model of prepubertal (P21) and adult (P80) male mice with the conditional deletion of the Insr and Igf1r genes in steroidogenic cells (<em>Insr/Igf1r-</em>DKO). In addition, male and female P21 mice with the samedeletion were used to monitor the expression of the main markers of mitochondrial biogenesis and fusion/architecture in Leydig cells, ovaries and adrenal glands. The results confirmed that deletion of <em> Insr</em> and<em> Igf1r </em> in steroidogenic tissues influences differentiation and functional characteristics of Leydig cells isolated from P21 and P80 mice, suggesting an appearance of "feminization". The number of Leydig cells isolated from both P21 and P80 <em>Insr/Igf1</em>r-DKO mice was reduced. Morphology and ultrastructure of Leydig cells were disturbed in P21 <em>Insr/Igf1r-</em>DKO mice. Steroidogenic capacity and activity, as well as expression of the main elements of steroidogenic machinery (<em>Lhcgr, Star, Cyp11a1, Cyp17a1, Hsd3b1 and 6, Hsd17b3, Sf1) </em>were decreased in Leydig cells from P21 and P80 I<em>nsr/Igf1</em>r-DKO mice, while the expression of transcriptional repressors of steroidogenesis (<em>Arr19</em> and <em>Dax1) </em>was increased in the same cells, but not in the rest of the testes. Transcription profile of the male sex markers (<em>Sry, Sox9</em>, <em>Amh</em>) was altered in Leydig cells from P21 and P80 <em>Insr/Igf1</em>r-DKO mice. Transcription of the female sex markers (<em>Rspo1, Wnt4</em>) in the testes, as well as <em>Cyp19a1 </em>expression and estradiol (E2) production in Leydig cells, from P21 and P80 I<em>nsr/Igf1</em>rDKO mice were increased. Transcription of mitochondrial biogenesis markers (<em>Ppargc1a, Tfam, Mtnd1</em>) was declined in Leydig cells from P21<em> Insr/Igf1r-</em>DKO mice, while changes were absent in the ovaries of the same genotype. Transcription of the same markers was increased in the adrenal glands of both sexes. The mitochondrial fusion/architecture markers (<em>Mfn1</em> and <em>Mfn2</em>) were increased in Leydig cells from<em> Insr/Igf1r</em>-DKO mice and followed by disturbedmitochondrial phase of steroidogenesis (progesterone production), as well as decreased number and disturbed morphology of mitochondria. Expression of the same markers in the ovaries was unchanged. In summary, results of this study showed that INSR and IGF1R are important in differentiation and steroidogenic function of Leydig cells from P21 and P80 mice. Also, these receptors are important regulators of mitochondrial biogenesis and fusion/architecture markers in steroidogenic cells of P21 male mice, but not in steroidogenic cells of ovaries.</p>
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Studium interakce inzulinu, IGF-1/2 a analogu IGF-1 s receptory inzulinu a IGF-1 / Interaction studies of insulin, IGF-1/2 and IGF-1 analogue with insulin and IGF-1 receptorsChrudinová, Martina January 2014 (has links)
Insulin-like growth factors 1 and 2 (IGF-1/2) are single-chain peptides exerting homology (in both amino-acid sequence and tertiary structure) to insulin. The main function of these peptides is promoting celular growth, proliferation and differentiation. Both insulin and insulin-like growth factors mediate their function through membrane receptors - insulin receptor (isoforms A and B) and IGF-1 receptor. All these receptors are members of the tyrosinkinase family of receptors and they exert the same subunit and domain composition. The activation of insulin and IGF-1 receptors is tightly associated with activation of two intracellular signaling pathways. The PI3-K/Akt pathway is involved in the glucose transport to the cell, induction of proliferation or inhibition of apoptosis, while the Ras/MAPK pathway is involved mainly in the induction of cell growth and differentiation. Due to the structure similarity in both the ligands and receptors, every ligand can activate different receptors (with different potency) and the signaling pathways associated with these receptors. Thus, the functions of IGFs and insulin, the same as their receptors, are overlapping. The distinct function of the concrete ligand can be distinguished by the different tissue distribution of both isoforms of insulin receptor and...
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Novel Intrinsic and Extrinsic Approaches to Selectively Regulate Glycosphingolipid MetabolismKamani, Mustafa 08 August 2013 (has links)
Glycosphingolipid (GSL) metabolism is a complex process involving proteins and enzymes at distinct locations within the cell. Mammalian GSLs are typically based on glucose or galactose, forming glucosylceramide (GlcCer) and galactosylceramide (GalCer). Most GSLs are derived from GlcCer, which is synthesized on the cytosolic leaflet of the Golgi, while all subsequent GSLs are synthesized on the lumenal side. We have utilized both pharamacological and genetic manipulation approaches to selectively regulate GSL metabolism and better understand its mechanistic details. We have developed analogues of GlcCer and GalCer by substituting the fatty acid moiety with an adamanatane frame. The resulting adamantylGSLs are more water-soluble than their natural counterparts. These analogues selectively interfere with GSL metabolism at particular points within the metabolic pathway. At 40 µM, adaGlcCer prevents synthesis of all GSLs downstream of GlcCer, while also elevating GlcCer levels, by inhibiting lactosylceramide (LacCer) synthase and glucocerebrosidase, respectively. AdaGalCer specifically reduces synthesis of globotriaosylceramide (Gb3) and downstream globo-series GSLs. AdaGalCer also increases Gaucher disease N370S glucocerebrosidase expression, lysosomal localization and activity. AdaGSLs, therefore, have potential as novel therapeutic agents in diseases characterized by GSL anomalies and as tools to study the effects of GSL modulation.
Two predominant theories have been developed to explain how GlcCer accesses the Golgi lumen: one involving direct translocation from the cytosolic-to-lumenal leaflet of the Golgi by the ABC transporter P-glycoprotein (P-gp, ABCB1, MDR1), and the other involving retrograde transport of GlcCer by FAPP2 to the ER, followed by entry into the vesicular transport system for Golgi lumenal access. To examine the in vivo involvement of P-gp in GSL metabolism, we generated a knockout model by crossbreeding the Fabry disease mouse with the P-gp knockout mouse. HPLC analyses of tissue Gb3 levels revealed a tissue-specific reduction in MDR1/Fabry mice. TLC analyses, however, did not show such reduction. In addition, we performed a gene knockdown study using siRNA against P-gp and FAPP2. Results show these siRNA to have distinct effects on GSL levels that are cell-type specific. These results give rise to the prospect of unique therapeutic approaches by targeting P-gp or FAPP2 for synthesis inhibition of particular GSL pathways.
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Novel Intrinsic and Extrinsic Approaches to Selectively Regulate Glycosphingolipid MetabolismKamani, Mustafa 08 August 2013 (has links)
Glycosphingolipid (GSL) metabolism is a complex process involving proteins and enzymes at distinct locations within the cell. Mammalian GSLs are typically based on glucose or galactose, forming glucosylceramide (GlcCer) and galactosylceramide (GalCer). Most GSLs are derived from GlcCer, which is synthesized on the cytosolic leaflet of the Golgi, while all subsequent GSLs are synthesized on the lumenal side. We have utilized both pharamacological and genetic manipulation approaches to selectively regulate GSL metabolism and better understand its mechanistic details. We have developed analogues of GlcCer and GalCer by substituting the fatty acid moiety with an adamanatane frame. The resulting adamantylGSLs are more water-soluble than their natural counterparts. These analogues selectively interfere with GSL metabolism at particular points within the metabolic pathway. At 40 µM, adaGlcCer prevents synthesis of all GSLs downstream of GlcCer, while also elevating GlcCer levels, by inhibiting lactosylceramide (LacCer) synthase and glucocerebrosidase, respectively. AdaGalCer specifically reduces synthesis of globotriaosylceramide (Gb3) and downstream globo-series GSLs. AdaGalCer also increases Gaucher disease N370S glucocerebrosidase expression, lysosomal localization and activity. AdaGSLs, therefore, have potential as novel therapeutic agents in diseases characterized by GSL anomalies and as tools to study the effects of GSL modulation.
Two predominant theories have been developed to explain how GlcCer accesses the Golgi lumen: one involving direct translocation from the cytosolic-to-lumenal leaflet of the Golgi by the ABC transporter P-glycoprotein (P-gp, ABCB1, MDR1), and the other involving retrograde transport of GlcCer by FAPP2 to the ER, followed by entry into the vesicular transport system for Golgi lumenal access. To examine the in vivo involvement of P-gp in GSL metabolism, we generated a knockout model by crossbreeding the Fabry disease mouse with the P-gp knockout mouse. HPLC analyses of tissue Gb3 levels revealed a tissue-specific reduction in MDR1/Fabry mice. TLC analyses, however, did not show such reduction. In addition, we performed a gene knockdown study using siRNA against P-gp and FAPP2. Results show these siRNA to have distinct effects on GSL levels that are cell-type specific. These results give rise to the prospect of unique therapeutic approaches by targeting P-gp or FAPP2 for synthesis inhibition of particular GSL pathways.
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