Growth Factors.docx

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Biological Sciences
Michelle Aarts

Growth Factors - Are peptide - Regulate the differentiation and growth of both CNS and PNS NGF is one member of a family of Neurotropins NGF Family and its receptors The gene family of neurotropins includes NGF, BDNF, NT-3 and NT-4. NGF : nerve growth factor BDNF: brain-derived neurotropic factor NT-3: neurotropin-3 NT-4; neurotropin-4 These factors are produced in limited amounts in target tissues Mediate cell interaction regulating neuron survival during period of naturally occurring neuronal death in development Release of these protein also regulates extent of innervations of the target tissues Neurotropins also have a function in adult CNS All are synthesized as precurosor polypeptides that are later cleave dto yield mature neurotropins All are homodimers of 115 to 130 aa residues Share alteast 50% sequence identity, including 6 conserved cysteine residues NGF acts directly through trk phosphorylation Muscle NT-4 is a physiological factor influencing”activity-dependent” changes in neuromuscular junctions i.e muscle activity mucle –derived NT-4 may act as an activity-dependent neurotrophic signal for growth and remodeling of adult motor neurons innervation Target-derived Neurotropic factors Treating chick embryos in vivo with crude and partially purified extracts from embryonic hindlimbs during normal cell death period rescues a significant number of motorneurons from degeneration. The survival activity of partially purified extract is dose-dependent and developmentally regulated The massive motorneuron death that occurs after early hindlimb removal is partially ameliorated by daily treatment with hindlimb extract.  Target-derived neurotropic factors are involved in regulation of motorneuron survival in vivo. Insulin and IGFs Insulin and IGF-1 and IGF-2 are required for optimal growth and proliferation of number of cell types Also stimulate proliferation of cultured sympathetic neuroblasts regulatory role in mitogenic cycle of neurblasts during fetal development As neurons differentiate terminally, they cease to divide but they still express receptors for insulin, IGF-1 and IGF-II Expression in the brain restricted to IGF-II and much less to IGF-I ~ Insulin and IGF’s play a major role in mature nervous systrm , includes functional maintenance and survival of neurons Apoptosis can be triggered by some Growth factors and hormones Apoptosis is a mode of cell death in which cells are deleted from tissues by a programmed sequence of biochem events Opposite to mitosis Plays a imp role in maintenance of renewable tissues Accounts for most or all of the programmed cell death responsible for tissue remodeling in vertebaretdevelopment The homeostatic balance of cell number is brough by presence/absence of specific hormones or growth factors i.e deletion of lymphocytes of b and T cell lineages during negative selection in the immune response is affected by apoptosis i.e lymphocytolysis evoked by glucocorticoids is a good example of hormone-mediated cell death.--> physiologically mediated cell death vs necrotic death from trauma drugs that block protein synthesis prevent apoptosis therefore programmed cell death requires specific proteins “suicide proteins” Hematopietic Growth Factors Hematopoiesis is the process of renewal and replacement of the cells and formed elements of blood Erythropoiesis is a subset of this larger scheme and includes only those events that lead from the appearance of the committed erythroid progenitor cell through the formation of red blood cells. Red and white blood cell differentiation and production are regulated by a number of hormones EP: a sialoprotien, 165 aa. Is a glycoprotein contains over 40% carbs, made of sialic acid and a number of suars The sialic residues are imp for bio activity in vivo as in the asialo form it is cleared too rapidly by the liver Found in blood and urine of mammalian species 1)Erythropoietin enhances the formation of new red blood cells - the red cell mass is always constant - exposing individuals to high altitudes (low oxygen or hypoxia) results in increased erythropoiesis Hyperoxia: results in reduced erythropoeisis Presence of an erythropoietic factor: parabiotic experiment/; where subjection of one rat to hypoxia resulted in increased erythropoiesis in its parabiotic partner.- suggests the existence of a humoral erythropoietic factor= erythropoietin [EP] Erythropoietin is elevated by conditions that create tissue hypoxia and decreased by conditions that create hyperoxia Agents that increase metabolic rats and oxygen consumption i.e thyroid hormones etc produce a state of increased need fro oxygen  under these conditions, EPis produced, leading to increased erythropoiesis - ratio of oxygen supply to oxygen need determine level of EP formation and hence stimulus to erythropoiesis KIDNEY & EP Kidney produces the erythropoietic factor = erythropoietin [EP] EP levels are reduced after hypophysectomy and is increased in response to growth hormone EP is also produced in response to androgen stimulation  An intrarenal sensor is thought to monitor the availability of Oxygen and translate this into altered rate of EP production  Evidence from studies suggests that a peritubular interstitial cell outside the tubular basement membrane was the renal cell that synthesized EP mRNA under basline or under hypoxia conditions  These cells in the cortex or outer medulla  Increased EP production related to increased number of cells producing the EP mRNA vs than the increased production of mRNA by EP-producing cells : increase in NUMBER of cells not in production -Kidney is primary source of EP but EP also originates in other tissues low basal rate of erythropoeisis is maintiend by anephric patients. External soruce: liver because liver source of fetal EP EP Physiological effect EP affects erythroid progentiors in the bone marrow by binding to the EP receptor (EPR) Early and late-stage erythroid progenitor cells differ in their responsiveness to EP because they express either truncated receptor or full-length EPR. A majority of early-stage erythroid progenitors expressing EPR-T may die of apoptosis but late-stage erythroid progenitors expressing EPR-F may survive and differentiate in to mature erythrocytes in same physio concn of EP.  ^ is a mechanism that appears to waste early-stage progenitors but forms a large reservoir of late-stage erythroid precursors Effects of EP are not noted until 2-3 days after stimulation because of the time it takes for reticulocytes to mature. Half-life of EP is only about 5 hrs- only a priming stimulus is needed not continuous erythropoietin for developing erythroblasts Role of EP is to enhance proliferation of erythrocyte precursor cells in bone marrow in to erythrobalsts and to stimulate proliferation of newly formed erythroblasts Erythroblasts are cells destined to become erythrocytes. Stimulation of RNA synthesis is the primary event in mechanism of EP action EP has primary effect on the plasma membrane of marrow cells to produce an active cytoplasmic protein intermediate that interacts with the nucleus to stimulate synthesis of a variety of RNAs. DNA synthesis, cell division etc follow in the responsive cell. … Thymic hormones Thymus gland: lobular gland, lies above the heart infront of the aorta In humans and mammals, the thymus begins to atrophy right after puberty. Removal of the gland in adult animal causes no harmful effects. Therefore, the thymus gland was thought to have no function but now thymus gland is an endocrine organ involved in development of immunological competence.--> thymus gland produces a hormone whose role is to activate lymphocytes for antibody production. THE THYMOSINS - Biologically active susbatcnes found within extracts of the thymus gland - A thymosin polypeptide [thymosin α1] from calf 28 aa and highly active acts on prothymocytes to induce differentiation to more mature Tcells [ t refers to thymus-derived] - Thymosin β4-> acts on stem cells to form prothymocytes - - being used in clinical tests with children who have some primary immunodeficiency diseases..>thymosins trigger maturational progression of several early stages of T-cell development and to increase the capacity of certain mature T cells to respond to antigens Platelet-Derived Growth Factor acts locally on injured blood vessels Whole blood serum is required for growth of certain cells in lab Serum prepared fromcell-free plasma has little or no mitogenic activity-> this activity can be restored by adding material released from blood platelets to sera therefore, the mitogenic principle in whole blood serum may be derived from platelets PDGF: Platelet-Derived Growth Factor - Is released from platelets during platelet aggregation in the process of blood clot formation - At sites of wounds, the platelets adhere to the endothelial lining of the blood vessel in such a way as to plug the defect”platelet adhesion” - Also release chemical m
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