Foundation 2 Week 3 part 3
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Where is loose connective tissue located, and what are its structural and cellular features?
- Loose connective tissue is primarily located beneath the epithelia that covers the body and lines the internal surfaces of the body. It is also found in glands and blood vessels.
- This is the site of inflammatory and immune reactions.
How do dense irregular and dense regular connective tissues differ in their locations, functions, and cellular and acellular components?
- Dense irregular: Contains mostly collagen fibers, bundled together in various directions (hence, irregular). There are few cells (most of which are fibroblasts). It is found mainly in the skin and mucosa of hollow organs where it provides resistance to tearing and stretches from different directions.
- Dense regular: Like irregular, it contains mostly connective tissue with little ECM, but it is bundled together in parallel arrays and densely packed to provide maximum strength in specific directions. It is most commonly found in tendons, ligaments, and aponeuroses.
Describe the different tissues formed by dense regular connective tissues.
- Tendons: Attach muscles to bone. Fibroblasts (called tendinocytes) lie between the fibers to provide repair.
- Ligaments: Attach bone to bone, and are less regularly arranged than tendons. Mostly made from collagen, but some also contain elastin.
- Aponeuroses: Resemble broad, flattened tendons, arranged in multiple layers with each layer rotated 90 degrees different than the previous. This is found in the cornea.
What is the significance of the amino acid sequence on the structure and function of the collagen fibril?
- Every 3rd amino acid is a glycine (except at the ends). The glycine is necessary for the triple helix as it allows each of the α chains to interact.
- The pattern is usually: (hydroxyproline or hydroxylysine) - glycine - proline
How do the alpha chains in collagen molecule differ?
- There are 42 different known types of α chains that vary in size (600-3,000 amino acids) which compose 28 known collagens.
- Collagen can be homotrimeric (having only one type of α chain) or heterotrimeric (having 2 or 3 different α chain types)
What is the sequence of events during intracellular synthesis of Type I collagen and the role of Vitamin C in the process?
- 1) Pro-α chains (preprocollagen molecules) are synthesized in the rER and then discharged into the cisternae of the rER.
- 2) Post translational modifications occur in the cisternae of the rER, including:
- -The amino-terminus is cleaved
- -Proline and lysine residues are hydroxylated. THIS REQUIRES VITAMIN C (ABSORBIC ACID)
- -O-linked sugar groups are added to hydroxylysine residues, and N-linked sugars are added to the terminal positions.
- -The globular structure is formed at the carboxy-terminus.
- -A triple helix is formed, starting at the carboxy-terminus.
- -Intra and interchain hydrogen and disulfide bonds form.
- -The chaperone molecule, hsp47, binds and stabilizes the triple helix. The molecule is now called procollagen.
- 3) The procollagen is excreted from the cell where procollagen peptidase from the cell membrane cleaves the uncoiled ends of the procollagen, forming mature collagen.
- 4) The collagen molecules then align together through a process called fibrillogenesis.
What is involved in the formation of the collagen fibril?
- The cell produces areas where collagen can aggregate (called “coves”) where the collagen self assembles in rows, head to tail.
- Covalent bonds then cross link the lysine and hydroxylysine aldehyde groups.
What cells synthesize collagen molecules?
Mostly connective tissue cells, including fibroblasts (chondrocytes in cartilage, osteoblasts in bone, pericytes in blood vessels). Epithelial cells produce the collagen molecules of basement membrane.
What are the two mechanisms and the molecules involved in the degradation of collagen?
- Proteolytic degradation: Occurs through matrix metalloproteinases (MMPs) enzymes. Triple-helical undenatured forms are resistant, so mostly the damaged forms are degraded.
- This includes collagenases, gelatinases, stromelysins, matrilysins, membrane type MMPs (produced by cancer), and macrophage mellatoelastases.
- Phagocytotic degradation: Macrophages or fibroblasts degrade parts of the ECM
What is caused by a defect in type I collagen.
Osteogenesis Imperfecta type I. Symptoms include very fragile bones (“fragile as a china doll”) that break often, hearing loss (due to ear bones breaking and fusing), blue sclera, weak tendons, and thin skin.
What is caused by a defect of type III collagen
Ehlers-Danos Syndrome Type IV. Symptoms include hypermobility of joints, pale thin skin, severe bruisability, and early morbidity and mortality from rupture of vessels and internal organs.
How does type III collagen differ from type I collagen as to structure and location?
- Collagen fibrils are composed of the stronger, type I collagen.
- Reticular fibrils are composed of type III, which contain a greater number of sugar groups which stain black (argyrophilic).
What are the 3 primary mechanisms of epigenetic regulation? Where are they most likely to be in use?
- DNA methylation: Can occur on any cytosine, but CpG islands (where C’s and G’s are together) are the primary target. Hypermethylation can persist from the parental germ line.
- Post translational modification of histones: Occurs when the binding of epigenetic factors to histone “tails” alters the extent to which DNA is wrapped around histones and the availability of genes in the DNA to be activated. Can be acetylation (-CH2CH3) of lysine residues, Methylation (-CH3), ubiquitylation, phosphorylation, sumoylation.
- Regulation by non-coding RNAs: All types of RNA except mRNA can affect the
What can be caused by disruption of normal ncRNA?
- •Alzheimer disease
- •Multiple sclerosis
- •Parkinson disease
- •Amyotrophic lateral sclerosis
- •Cardiac arrhythmias
- •Heart failure
- •Many single gene disorders
What is Rb, and what does it do?
- Rb is a tumor suppressor gene (codes for retinoblastoma protein) that regulates passage through the G1/S restriction point.
- Inactivation of both copies of the gene results in a retinoblastoma.
- Retinoblastoma protein sequesters E2F transcription factors.
- Lack of Rb and excess E2f activity results in tangled chromosomes and aneuploidy.
What are the differences between malformations, syndromes, disruptions, deformations, and sequences? What is the recurrence risk for each?
- Malformation: Structural defect of an organ resulting from the abnormal formation of tissues. Can be major (needs surgery) or minor. Three or more minor malformations raise concerns.
- Syndrome: Multiple anomalies that occur independently rather than sequentially due to a single basic cause. Risk of recurrence: 3-5%
- Disruption: A structural defect resulting from tissue damage and breakdown of otherwise normal structures. Can be caused by an amniotic band. The risk of recurrence << 1%
- Deformation: An abnormality in form or position of a body part caused by mechanical force or secondary effects from a functional abnormality in the fetus.
- Sequence: A structural defect or mechanical factor which leads to a sequence of secondary effects.
Define uniparental disomy. What happens in an embryo if it involves a segment of a chromosome, an entire chromosome, the entire genome?
- Uniparental disomy (UPD): When both copies of a chromosome come from the same parent.
- This can occur when trisomy is rescued by loss of the 3rd chromosome.
- Parent-of-origin genes can be effected with both genes being active or both genes being inactive (same effect as deletion).
- Entire maternal UPD results in teratomas.
- Entire paternal UPD results in hydatidiform of placenta
What role does epigenetics play in cellular differentiation? What role does imprinting play in the cloning of organisms and stem cells?
- Oocyte and sperm have CpG methylation. The sperm quickly demethylates, but the Oocyte takes more time. At the first DNA replication, remethylation begins.
- Imprinting can cause one parents genes to be expressed more or less.
What are HOX genes?
Developmental transcription factors (an X as the third letter always suggests its a transcription factor). Each gene has two exons. The second exon has a homeobox (DNA sequences involved in the regulation of anatomical patterns).
How do HOX gene clusters work?
We have 39 HOX genes in four clusters (A,B,C,D) on four chromosomes. They work in sequence to promote growth of different areas during development.
What are morphogen?
Small diffusing molecules that bind to inducible transcription factor receptors. Includes retinoic acid, steroid hormones, and thyroxine.
What is the role of Sequential Induction?
Parts of the HOX gene are induced sequentially to generate limb growth and development. (ie, genes for the head are induced before genes for the back, and the start of a limb is induced before the end of a limb.
What are the activators and inhibitors of angiogenesis?
- Activators: VEGF. FGFn TFG-ß, IL-8, Angiopoietin, Angiogenin, PDGF
- Inhibitors: Angiostatin, endostatin, Thrombospondin, interferon α/ß, collagen 4 fragments
Compare the properties of tumor capillaries with normal capillaries.
Tumor capillaries: 3x the diameter, disorganized, loosely associated with pericytes gaps of several microns between cells, walls are up to 10x more permeable, higher interstitial fluid pressure, poor lymphatic drainage.
Describe how tumor cells induce angiogenesis
- Hypoxia causes tumor cells to recruit normal endothelial cells to release angiogenic factors.
- Angiogenic factors cause MMP to break down nearby ECM and epithelial cells to gather to form blood vessels.
- Cells monitor O2 tension and release angiogenic factors (such as Vascular Endothelial Growth Factor (VEGF)) when needed. This causes endothelial cells to undergo mitosis and translocate to build blood vessels. They also release MMP to break down ECM and make room.
What processes depend upon angiogenesis?
Embryonic development, implantation of placenta, wound healing, disease processes (diabetic retinopathy, psoriasis, rheumatoid arthritis, tumorigenesis).
Describe the role of angiogenesis in tumorigenesis.
Epithelium is avascular, but gives rise to carcinomas (about 80% of all tumors). 90% of the cells in a carcinoma are normal tissue stromal cells that communicate through heterotypic interactions. If tumor cells are located more than 0.2 mm from vessels, they will die from hypoxia.
Define the angiogenic “switch”.
Normal conditions prevent angiogenesis, so the normal inhibition must be overcome. When angiogenic factor influence outweighs anti-angiogenic factors, angiogenesis begins.
Describe the importance of chemotherapeutic targeting of angiogenesis.
- Endostatin has been shown to decrease tumors in mice. Inhibitors can be used to fight tumors.
- Normal adult endothelial capillary cells replicate about once every 1000 days. Tumor endolthelial cells turn over every 50-60 hours.
- Possible therapies include:
- Drugs that block angiogenic factors (like VEGF-antibodies)
- Drugs that block breakdown of ECM
Describe different anti-angiogenic factors and functional roles.
- Thrombospondin-1: Secreted by many cell types and binds to molecules in the ECM. It binds to CD36 on endothelial cells to inhibit proliferation.
- Thrombospondin-1,2, interferon α/ß, arrestin, tumstatin, angiostatin, endostatin, fibulin, endorepellin, TIMP-2
What is the role of myofibroblasts?
- Myofibroblasts have the characteristics of both smooth muscles and fibroblasts.
- They provide force generation to close the wound.
How do you calculate ABI?
- ABI = Systolic BP at ankle / Systolic BP at arm
- Normal range = 1-1.2
- Immediate care is required when ABI < 0.5
- Lower values indicate arterial disease.
How is local anesthesia applied?
- using lidocaine or epinephrine.
- Epinephrine should be avoided in fingers and toes.
What comprises the core of a microvillus and the terminal web to which they are connected?
Microvilli contain a core of 20-30 actin filaments with villin (an actin-bundling protein) at the tip and the terminal web (a horizontal network of actin filaments) at the bottom. In other words, the core and terminal web (bottom area) are composed of actin filaments.
What are the components, functions and locations of stereocilia?
- Stereocilia are composed of unusually long microvilli supported by bundles of actin-filaments anchored to the membrane by ezrin proteins.
- Male reproductive system: facilitate absorption via long processes
- Inner ear: sensitive to mechanical vibrations so can serve as sensory mechanoreceptors
- Stereocilia are limited to the male reproductive system and the inner ear. Specifically, they are found in the epididymis, the proximal part of the ductus deferens, and the sensory (hair) cells of the inner ear.
How do primary cilia function as receptors for fluid movement?
- Primary cilia (9+0 pattern of microtubules which means they have no central pair of microtubules) extend from the surface of epithelial cells that line secretory ducts into the extracellular lumen. The flow of fluid causes them to passively bend and generate a signal.
- For example: primary cilia found in the glomerulus and tubular cells of the kidney function as mechanoreceptors. Fluid flows through the renal corpuscle and tubules cause them to bend, which initiates and influx of calcium into the cell.
What is the defect in primary cilia that can lead to polycystic kidney disease?
- Primary cilia normally function as mechanoreceptors in the glomerules and tubular cells of the kidney.
- Autosomal recessive mutations in ADPKD1 and ADPKD2 affect polycystin-1 and polycystin-2, which are necessary for calcium channel formation in primary cilia.
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