Raghda Al-Droubi Marwa Abo Zour

Transcription

1 Raghda Al-Droubi Marwa Abo Zour

2 Tissue repair (2 of 4)

3 What will we discuss today? Growth factors migration بأثروا على الخال ا عشان حفزوا ال proliferation extracellular matrix و ال و التحول من مكان آلخر اضافة الى تكو ن ال Role of the extracellular matrix in tissue repair ECM ه عبارة عن شغلت ن اساس ت ن : Basement membrane matrix interstitial (ما ب ن الخال ا)

4 Growth factors They promote entry of cells into the cell cycle They relieve blocks on cell cycle progression P53 GF ال P53 (genome guardian) ***النه ال cell cycle بدها اش وقفها متل ال رح ش ل ال They prevent apoptosis بمنعوا ال apoptosis النهم بدهم الخل ة تفوت ال cell cycle و تنقسم و الخ. مو تموت They enhance the synthesis of cellular proteins in preparation for mitosis ) blocks احنا بنحتاج transcription\translation تكو ن بروت نات )ال همه عبارة عن للخل ة او انز مات Protein synthesis :1- structural component ( blocks) 2-functional proteins ( enzymes) رح حفزوا ال proliferation of cells عن حفزوا انقسام الخال ا و خلوهم دخلوا ال cell cycle ال ه ه عبارة عن تضاعف ال DNA و ما تبعه من mitosis cell cycle رح ش لوا ال blocks عن ال

5 Growth factors proto-oncogenes mostly stimulate **بشكل عام ال GF بحفزوا ج نات موجودة ف كروموسومات الخل ة هاي الج نات اسمها **ف الخال ا السرطان ة اسمهم oncogenes **هدول الج نات (proto-oncogenes) بتصنع بروت نات تتحكم ف ال Growth A major activity is: to stimulate proto-oncogenes *They are growth control genes *Mutations in them unrestrained cell proliferation characteristic of cancer (oncogenesis) cancer مهم ن جدا ف ال Proto-oncogenes ** انه بص ر لهم mutation و بتحولوا ل oncogenes و بص ر عندي تكاثر للخال ا بشكل غ ر مس طر عل ه و غ ر متوقف Tumor suppressor genes P53** رح صنعول اش اء تعاكس عمل ة ال oncogenesis (cancer) Produced by -macrophages -lymphocytes -parenchymal cells -stromal (connective tissue) cells recruited to the site of injury or are activated at this site, as part of the inflammatory process in response to cell injury هدول هدفهم تعو ض ال injury

6 Selected growth factors Autocrine VS Paracrine VS Endocrine signaling Not only from platelets Robbins basic pathology 9 th edition modified

7 الخل ة تفرز اش شتغل على نفس الخل ة : Autocrine الخل ة تفرز اش شتغل على خل ة مجاورة : Paracrine الخل ة تفرز اش مش ف الدم و بأثر على خل ة بع دة Endocrine:

8 Signaling Mechanisms of Growth Factor Receptors These are for plasma membrane receptors **ارتبطت ب اش اء قدرت تمرق من ال membrane *Intracellular receptors: their ligands are hydrophobic vitamin D steroid thyroid hormones hormones Robbins basic pathology 9 th edition modified Usually monomeric

9 Receptor with intrinsic kinase activity GPCRs Receptor without intrinsic kinase activity 1- بص ر ف ها تكون ل dimer 2- جزء منه بتحفز و بحفزل pathway 1- تذكروا عالقته بال cytokines 2- االنز م ما ف ه جواته tyrosine kinase 3- بكون ف ه receptors لل cytokines بالعاده اما ال chemokines ف ال GPCP 4- بعد ال ligand binding بحفزل tyrosine kinases مو من داخل ال receptor نفسه بكون اسمهم ال JAK بعملوا kinase phosphorylation بحفز transcription factor ال هوه ال STAT

10 Signaling mechanisms, cont d Receptors with intrinsic kinase activity binding of ligand dimerization phosphorylation of the receptor subunits the receptor binds and activates other intracellular proteins Kinase activity جواته بعمل phosphorylation ل جزء منه > وجزء بفسر جزء < phospholipase Cγ *PLC-γ]) RAS Phosphatidylinositol 3[PI3]-kinase Proto oncogene مهم جدا ف ال cancer Transcription

11 Signaling mechanisms, cont d G protein coupled receptors seven-transmembrane α-helix segments = seven-transmembrane receptors لما رتبط ف ال ligand ؤدي الى استبدال ال GDP بال GTP و بص ر ACTIVE binding to ligand the receptors associate with intracellular guanosine triphosphate (GTP)- binding proteins (G proteins) that contain guanosine diphosphate (GDP) exchange of GDP with GTP activation of the G proteins inositol 1,4,5-triphosphate (IP3) Release of calcium from the ER This is the largest family of plasma membrane receptors cyclic AMP (camp) GDP >> inactive GTP >> active

12 Role of the Extracellular Matrix in Tissue Repair الذراع االخز لعملية ال repair Two basic forms: بتكون من بروت ن ن مهم ن جدا : 1- type four collagen (non fibrillary and non lamellar) 2-Lamin or proteoglycan Major 3 components: -interstitial matrix -basement membrane 1-Collagen ( fibrillary non fibrillary) 2-Elastin 3-proteoglycan 4-hyaloronane 5-Fibronectin -fibrous structural proteins such as collagens and elastins -water-hydrated gels such as proteoglycans and hyaluronan tensile strength and recoil resilience and lubrication -adhesive glycoproteins connect the matrix elements to one another and to cells

13 Extracellular matrix Amorphous & non-lamellar ل س على شكل طبقات Also: non-fibrillary collagens and fibronectin Robbins basic pathology 9 th edition modified

14 Collagen 3 separate polypeptide chains braided into a ropelike triple helix 30 collagen types have been identified Some collagen types (e.g., types I, II, III, and V) form fibrils by virtue of lateral cross-linking of the triple helices = fibrillary collagens covalent bonds catalyzed by the enzyme lysyl-oxidase needs vitamin C >> particularly in healing wounds and in scars مهم ف عمل ة ال cross-linking هذه العمل ة ألنه مهم لالنز م المسؤول عن

15 Collagen, cont d Vitamin C deficiency???? wound healing, gum, eyes Scurvy VC ؤدي الى مشاكل ف : االسقربوط : نقص Ehlers-Danlos & osteogenesis imperfecta الناس ال جلدهم بكون مرخ كت ر genetic defects in fibrillary collagens *Examples of non-fibrillary collagens: type IV basement membrane type IX intervertebral discs type VII dermal-epidermal junctions

16 Elastin The ability to recoil Walls of large vessels recurrent pulsatile flow Uterus, skin, ligaments.etc. Central core of elastin + surrounding fibrillin glycoprotein Its defect will cause.marfan syndrome Normal trunk with very long arms and legs, problems in aorta

17 Proteoglycans and hyaluronan جزء كربوهيدات وجزء بروتين Proteoglycans: highly hydrated compressible gels : امتصاص الصدمات باالضافة الى ال lubrication e.g., cartilage in joints long polysaccharides, called glycosaminoglycans or mucopolysaccharides (examples are dermatan sulfate and heparan جزء البروت ن ), linked to a protein backbone جزء الكربوه درات sulfate

18 Proteoglycans and hyaluronan, cont d Hyaluronan = hyaluronic acid huge mucopolysaccharide without a protein core *Proteoglycans : provide reservoirs for growth factors secreted into the ECM (e.g., fibroblast growth factor [FGF], HGF) من مهماته: ارتباطه مع ال GF *Some proteoglycans are integral membrane proteins roles in cell proliferation, migration and adhesion by binding growth factors and chemokines بعضهم بكونوا موجود ن ف غشاء الخل ة و ساعدوا ف عمل ة ال adhesion

19 Adhesive Glycoproteins and Adhesion Receptors Fibronectin of interstitial ECM Laminin of basement membrane *Adhesion receptors: cell adhesion molecules (CAMs) 4 families: -Immunoglobulins -Cadherins -Selectins -Integrins

20 Fibronectin Disulfide-linked heterodimer Produced by different cell types Tissue and plasma forms Domains for binding ECM components, e.g., collagen, proteoglycan etc. and for binding cellular integrins (via tripeptide arginine glycine aspartic acid (abbreviated RGD) motif) ** رتبط بال fibrin من خالل تسلسل حمض ام ن مع ن (RGD) ** رتبط Fibronectinمع ال fibrin ال داخل ال, clot وارتباطه شكل منصة لحدوث تفاعالت عل ه مثل ال : healing tissue Tissue fibronectin forms fibrillar aggregates at wound healing sites Plasma fibronectin binds to fibrin within the blood clot that forms in wound, providing the substratum for ECM deposition and reepithelialization

21 Laminin The most abundant glycoprotein in basement membrane Connects cells to underlying ECM components such as type IV collagen and heparan sulfate Laminin can also modulate cell proliferation, differentiation, and motility

22 Integrins Transmembrane heterodimeric glycoprotein chains The main cellular receptors for ECM components, such as fibronectins and laminins Present in the plasma membrane of most cells, with the exception of red blood cells Bind to many ECM components through RGD motifs, initiating signaling cascades that can affect cell locomotion, proliferation, and differentiation Intracellular domains link to actin filaments, thereby affecting cell shape and mobility بسبب حدوث تغ رات ف ال cytoskeleton

23 Functions of the Extracellular Matrix Mechanical support for cell anchorage and cell migration, and maintenance of cell polarity Control of cell proliferation by binding and displaying growth factors by signaling through cellular receptors of the integrin family منصة لحدوث التفاعالت Scaffolding for tissue renewal disruption of the ECM results in a failure of the tissues to regenerate and repair by scar formation Establishment of tissue microenvironments e.g., The basement membrane forms part of the filtration apparatus in the kidney تشكل ب ئة مع نة لحدوث وظائف مع نة

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