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Foundations 2 Week 1: Cell Proliferation + Wound Healing
Terms in this set (145)
what are the 2 phases of the cell cycle?
Mitosis (prophase, metaphase, anaphase, telophase, cytokinesis)
Interphase (G1, S, G2)
how long does the S phase (DNA replication) of mitosis last? (___ hours, encompassing ___ of the total cell cycle time)
8-12 hours (1/2 the total cell cycle time)
how long does the M phase (mitosis) last?
In which cell cycle phase does organelle duplication occur?
the cell cycle takes a VARIABLE amount of time on average in different tissues (especially cancer). How long does it last in:
1) bone marrow progenitors
2) intestinal epithelium
3) bronchial epithelium
1) bone marrow progenitors: 12-24h
2) intestinal epithelium: 12-14h
3) bronchial epithelium: 9-10 days
4) hepatocytes: 150 days
5) cardiomyocytes: NEVER (unassisted) - heart muscle doesn't regenerate
cells that have completely lost their ability to proliferate
extracellular chemicals that stimulate cell division
heterodimeric protein kinases present in all phases of the cell cycle, will turn the cell cycle on and stimulate cell division
Cdk (cyclin-dependent kinase) complexes
Ex: M-Cdk, S-Cdk, G-Cdk - they are all activated by cyclin, which forms their regulatory subunit. Binding of cyclin changes the configuration of Cdk's T-loop, allowing the complex to be fully activated by CAK (Cdk-activating kinase) phosphorylation
both INK4 and Cip/Kip (ex: p27) turn Cdk ___ (on/off - what effect does it have on the cell cycle?)
off - INK4 and Cip/Kip proteins inhibit cell cycle progression
The SCF complex is an E3 ubiquitin ligase that tags ___ (molecule) for degradation by proteasomes - what effect does this have on the cell cycle?
p27 (a Cip/Kip protein that inhibits Cdk) - this will turn the cell cycle on. Too much SCF can cause cancer (p27 is a tumor suppressor, SCF is an oncogene)
SCF is also responsible for degradation of Cdc6 during the S-phase, thus acting as a stopgap for further DNA replication
The APC Cyclosome is an E3 ubiquitin ligase that tags ___ (3 molecules) for degradation by proteasomes - what effect does this have on the cell cycle?
M-cyclin (and residual S-cyclin), as well as securin, ultimately turning the cell cycle off by turning anaphase on
*securin binds to separase, which cleaves the cohesin complex keeping the homologous chromosomes together until metaphase/anaphase
3 molecules activated by the myc gene
cyclin D, G1-Cdk, and SCF ubiquitin ligase --> all of these will push the cell cycle forward from G1--> S phase
G1-Cdk acts on ___ to push the cell cycle forward
Rb (retinoblastoma protein) - G1-Cdk will downregulate it, leaving more E2F proteins free to activate transcription of G1/S-cyclin
point in the G1 phase after which the cell is COMMITTED to the cell cycle and external stimuli can no longer affect cell proliferation
Which phase is mitogen-dependent and which is mitogen-independent?
restriction point (R)
G1-->S transition is mitogen-dependent, and S-->M is mitogen-independent
E2F is a transcription factor (normally inactivated by Rb) that activates transcription of ___ (what does this do to the cell cycle?)
G1/S-cyclin (turning the cell cycle on)
What proteins make up the pre-RC (pre-replication complex), and what does it do?
The pre-RC, which activates during the S-phase, is made up of the ORC (origin recognition complexes)/helicase, Cdc6, and MCM proteins --> these are important for unwinding the 2 DNA strands, allowing DNA polymerase to bind DNA and begin replication
what is the purpose of S-Cdk during the S-phase?
phosphorylates Cdc6 (causing it to be REMOVED from the pre-RC and degraded via SCF), as well as delocalizes MCM far away from DNA --> net effect is to prevent further DNA replication because we don't want extra copies of the genome
how is M-Cdk activated?
Cdc25 phosphatase and CAK (Cdk-activating kinase) are both activators of M-Cdk.
M-Cdk starts out in an inactive form (from the joining of M-cyclin and Cdk1) that is kept in check by Wee1 kinase until the replication fork is complete. Once that happens, Polo kinase activates Cdc25 --> active M-Cdk, which has negative feedback on Wee1 and positive feedback on Cdc25
what is the purpose of M-Cdk during mitosis?
induces mitotic spindle formation, chromosome condensation, nuclear envelop breakdown, and organelle distribution
activates APC ubiquitin ligase, which degrades securin to initiate anaphase
APC needs to be attached to ___ during mitosis in order to target securin for destruction
Which molecule(s) act to block APC destruction of securin until proper attachment of kinetochores to the mitotic spindle is assured?
Mad1/Mad2 block Cdc20-APC induced destruction of securin by a) binding unattached kinetochores and b) sequestering Cdc20 away from the APC
what phase of mitosis is cohesin cleaved in?
neovascularization is the growth of new blood vessels (usu capillaries), and is vital for embryonic growth, reproduction, and tissue repair. What are 2 main ways neovascularization can occur, and which cells are responsible for these pathways?
1) Vasculogenesis (de novo blood vessel formation, formed from EPCs/endothelial progenitor cells recruited from bone marrow)
2) Angiogenesis (vessel formation from existing vessels, formed from ECs/endothelial cells in blood vessels activated by growth factors
2 mechanisms that can activate angiogenesis
- hypoxia (low O2 activates HIF/hypoxia-inducible factor)
- inflammation (pro-angiogenic mediators: most importantly VEGF, but also includes Ang-2, FGF, and chemokines)
basic process of angiogenesis (4 steps) and main molecules mediating this
1) loosening of EC junctions to allow tip EC migration (VEGF)
2) degradation of ECMs to allow the stalk to grow out (MMPs)
3) tip cell migration (VEGF + Notch)
4) re-deposition of basement membrane and pericytes (PDGF, Ang-1)
VEGF, bFGF, PDGF, IL-8, HGF, and PIGF are all examples of growth factors that stimulate pro-angiogenesis through what mechanism?
indirect stimulation of supporting cells (cytokines can call on inflammatory cells to increase local VEGF concentrations; GFs can recruit pericytes to support angiogenesis)
VEGF and FGF ___ angiogenesis
Thrombospondin-1,-2; interferon alpha/beta; endostatin; angiostatin; and collagen IV ___ angiogenesis
pro-angiogenic molecule that stabilizes under hypoxic conditions, combining with other proteins to form a pro-angiogenic transcription factor
HIF (hypoxia-inducible factor)
explain the starvation hypothesis
anti-angiogenic drugs can cause tumor regression because tumors need constant new growth of blood vessels to continue growing
VEGF (vascular endothelial growth factor) binds to multiple endothelial receptors to activate tyrosine-kinase signaling, which mediates ___ (4 functions)
- endothelial cell survival
- vascular permeability
- cell migration
3 ways to reduce angiogenesis (i.e. 3 therapeutic targets for anti-angiogenesis drugs)
1) block VEGF directly (binding the ligand)
2) block the tyrosine kinase receptor that VEGF activates (using small-molecule RTKIs/receptor tyrosine kinase inhibitors)
3) inject endogenous inhibitors into the affected cell itself
what is main function of the monoclonal Ab/drug Avastin/bevacizumab?
binding VEGF to inhibit angiogenesis
Note: primarily used for metastatic colon cancer, as well as in combination chemotherapy for renal cell carcinoma, non-small cell lung cancer, and glioblastoma
what is the main function of the drug Sunitinib/Sutent? (multi-target)
inhibition of multiple receptor tyrosine kinases, ultimately inhibiting angiogenesis
RTKs include: VEGFR-1, -2, -3; PDGFR-alpha/beta; c-KIT
Note: used to treat renal cell carcinoma, pancreatic neuroendocrine tumors, and Gi stromal tumors
what is the main function of the drug Sorafenib/Nexavar? (multi-target)
inhibition of multiple receptor tyrosine kinases, ultimately inhibiting angiogenesis
RTKs include: VEGFR-1, -2, -3; PDGFR-beta; c-KIT; raf-1 kinase
Note: used to treat advanced renal cell carcinoma and unresectable hepatocellular carcinoma
anti-VEGF drugs also induce "normalization" of the vasculature, which increases drug delivery to the tumor. What would we find in abnormal tumor vessels?
tumor vessels will:
- have more vessels overall
- be disorganized and "tortuous" (winding)
- extremely permeable
- have abnormal basement membrane and pericyte coverage
--> overall result in an increase in IFP (interstitial fluid pressure), which is terrible for drug delivery
tumors can be resistant to anti-angiogenic drugs - explain 2 types of resistance
1) intrinsic resistance - tumors have pre-existing non-responsiveness, can have too many blood vessels or naturally exist with too few (grow without needing nourishment from blood vessels)
2) evasive/acquired resistance - tumors develop resistance over time due to hypoxic stimulation of ALTERNATE PATHWAYS of angiogenesis (GFs other VEGF can stimulate angiogenesis) - solution is to use combination therapies
4 (or 5) cardinal signs of inflammation
1) Heat (calor)
2) Redness (rubor / erythema)
3) Swelling (tumor / edema)
4) Pain (dolor)
5) loss of function (function laesa)
very first step in wound healing
hemostasis - platelets will activate thrombin, which cleaves fibrinogen into fibrin to form a clot to plug damaged vessels and provide a provisional matrix. Platelets also release contents of alpha-granules, which contain inflammatory GFs and cytokines
name 2 resident inflammatory cells (i.e. constantly present in connective tissue)
mast cells; macrophages
Note: these are triggered by injury or infection to release inflammatory mediators (cytokines/chemokines), which cause vasodilation and increased vascular permeability --> increased fluid and RBC leakage, contributing to local redness and swelling
name 2 circulating inflammatory cells (present in bloodstream, will migrate into inflamed tissue with help from adhesion molecules)
Note: neutrophil migration is known as extravasation/diapedesis, and these circulating inflammatory cells release inflammatory mediators responsible for local pain during infection
2 classes of danger signals recognized by resident inflammatory cells; a common pattern recognition receptor that recognizes these danger signals
PAMPs (pathogen-associated molecular patterns) - external signals
DAMPs (damage-associated molecular patterns) - internal signals
- recognized by TLRs (Toll-like receptors)
mast cells release ___ to increase vascular permeability
histamine + heparin
what is the difference between cytokines and chemokines?
chemokines encourage migration of cells towards the site of inflammation (CHEMOTAXIS)
- 2 examples of chemokines: IL-8, MCP1 (macrophage chemoattractant protein-1)
name 2 adhesion molecules important for diapedesis (leukocyte recruitment)
selectin - attaches to/slows down leukocytes, causing them to roll towards the cell surface
integrin - upon activation during inflammation, they will enter a high-affinity state and bind tightly to leukocytes, allowing them to find a nice place on the endothelial surface to transmigrate into
--> once in the tissue, the leukocyte will migrate in the direction of chemokines where it can pinpoint the site of injury and begin cleanup + repair
___ is the major growth factor responsible for fibrosis (hypertrophic scars or keloids)
___ are the 3 main growth factors responsible for re-epithelialization (during the proliferative stage of wound healing) - what cell type secretes these GFs?
- EGF (epidermal GF)
- KGF (keratinocyte GF)
- TGF-alpha (transforming growth factor-alpha)
--> secreted by keratinocytes
Notes: MMPs (matrix metalloproteinases) aid this process by breaking down the clot to provide space for keratinocyte migration
what cell type secretes angiogenic GFs (e.g. VEGF, FGF)?
endothelial cells (ECs)
___ are the 3 main growth factors responsible for collagen deposition - what cell type secretes these GFs?
--> secreted by fibroblasts
family of Zn-dependent peptidases that cleave ECM proteins
what molecule inhibits these?
MMPs (matrix metalloproteinases)
- MMP-1, -8, -13 all cleave fibrillary collagen (I and III)
TIMP (tissue inhibitor of metalloproteinases)
what is the function of TGF-beta1 and 2? What about the function of TGF-beta3?
Note: this is in the context of SCAR FORMATION
TGF-beta1 + 2: INCREASE ECM synthesis by activating fibroblasts, stimulating collagen deposition, increasing myofibroblast numbers, decreasing MMPs/increasing TIMPs
TGF-beta3 has the exact opposite function and reduces scar formation/ increases ECM degradation
what are contractures?
a form of abnormal scarring where normal elastic ECM in the skin is replaced by inelastic scar tissue - this results in limited mobility around the joints, which may affect the underlying muscles and tendons
fetal skin prior to the ___ of pregnancy is capable of TRUE regeneration with no inflammation or scar formation
< third trimester
Note: lower invertebrates e.g. lizards form a BLASTEMA (mass of undifferentiated cells) to regenerate lost body parts
standard of care for a laceration wound on someone's bare knuckles (Assuming they've been fighting)
assuming a fight, the laceration wound on their knuckles should be infected and should NOT be sutured - just clean the area of any blood clots and foreign material, irrigate gently, and try to decontaminate. Administer a local anesthetic and atraumatic technique of wound closure (sterile dressings, immobilization)
type of injury where a superficial layer of tissue is removed (ex: 1st degree burn)
Note: treatment is non-surgical - clean the wound and use moist dressings, as well as topical antibiotic to aid healing
what type of contusion requires treatment?
expanding hematoma - because it can damage overlying skin
injuries where sections of the tissue is torn off, either partially or in total
avulsions (partial or total - for total avulsion, keep amputated part in clean bag and put on ice; for partial avulsion, gently clean and irrigate the tissue, then reattach the flap to its anatomical position with a few sutures)
puncture wounds, especially made by rusted metal, are risky because of the possibility of ___ infection
what is the difference between primary, secondary, and tertiary intention?
primary - wounds sutured shut; fibrin seals the wound in 1-2 days, SHORTER inflammatory phase
secondary - no effort made to approximate epithelium, PROLONGED inflammatory phase, wound closes by contracture of myofibroblasts, deposition of granulation tissue
tertiary - wound deliberately left open, aka "delayed primary closure"; used for skin grafting or determining if the wound is infected, which would contraindicate primary closure
diabetic wounds sometimes have prolonged inflammation because of a defect in which step of inflammation resolution?
cleanup of apoptotic cells - there's a lot of debris in diabetic wounds that can result in gangrene/necrosis
wound infection is defined as ___ CFU/g (colony forming units per gram tissue)
Note: this measure is taken AFTER debridement (getting rid of necrotic tissue or dirt). Quantitative cultures of tissue samples should be taken for wounds stalled 2 weeks or more
a dense community of bacterial aggregates adherent to a surface or each other - this significantly contributes to wound infection and are challenging to treat because they cannot be penetrated by antibiotics or immune cells
common cause of varicose ulcers ("full-thickness defect of the skin in the anke region, common over the medial malleolus, that fails to heal spontaneously and is sustained by chronic venous disease")
improper functioning of the venous valves, usually in the lower limbs
common cause of arterial ulcers
atherosclerosis - basically any type of acute or chronic arterial INSUFFICIENCY
Note: we measure arterial insufficiency by taking the patient's ABI (ankle-brachial index)
how do you calculate the ABI (ankle-brachial index)?
systolic BP at ankle / systolic BP in arm
Note: used to measure arterial insufficiency, a major cause of arterial ulcers. API is an indicator of the patient's ability to heal
what are 3 causes of diabetic ulcers, which can lead to gangrene?
- peripheral neuropathy
- vascular disease
Note: diabetic ulcers are the MOST COMMON foot injuries leading to LOWER EXTREMITY AMPUTATION
how do you clean and prepare the wound for assessment?
- use surgical solution to clean surrounding skin
- use PHYSIOLOGICAL solution to clean actual wound (ex: normal saline)
- remove dirt, gravel, or foreign objects that can cause traumatic tattooing
list some different methods of debribement (the removal of foreign material/necrotic tissue and excision of ragged edges to prepare for wound realignment)
- surgical debridement
- mechanical (hydrotherapy, wet-to-dry dressing)
- autolytic (chemical agents breaking down dead tissue)
- enzymatic (collagenase, fibrinogen/deoxyribonuclease, papain/urea)
- biological (maggot therapy)
it's important to keep wounds moist with occlusive dressings (this increases epithelialization, matrix synthesis, and prevents scabbing), but excessive exudate inhibits production of key wound healing cells. How can we treat this?
vacuum therapy - using negative pressure devices and vacuum-assisted devices, as well as a drain to absorb exudate
only ___% of the genes we see clinically actually present with classic Mendelian genetics
the failure of a phenotype to manifest even with the genotype present
what is the term for a nonpenetrant individual who transmits the disorder to their offspring?
3 explanations for nonpenetrance (which is associated with DOMINANT phenotypes), and which reason makes up the majority of examples we see in the field
1) disease expression favors one sex (hereditary breast/ovarian cancer)
2) modifier genes and polymorphisms influence phenotypic expression (this is the majority!)***
3) environmental trigger needed to activate (adult-onset diabetes; lung cancer)
mutation causing achondroplasia
G380-->R in the FGFR3 gene
- results in defective chondrocyte differentiation and growth retardation of long bones - 80-90% of cases are caused by de novo mutations
mutation causing thanatophoric dysplasia
Type 1 - new cysteine residue introduced
Type 2 - Lys650Glu
- completely results from de novo mutations, produced by a LOF mutation in FGFR3
- the most common lethal skeletal dysplasia, no survival and therefore no inheritance
how can you distinguish a germline mosaicism from a de novo mutation?
if a second child with the same parents is afflicted with the same disease
- rate of germline mosaicism is as high as 5-15%
early somatic mosaicisms will affect ___, whereas later somatic mosaicisms will affect____
- which is a more common major cause of adult-onset disease?
early - entire regions of affected cells
later - single organs or tissues *** <-- this is a major cause of adult-onset disease
explain allele heterogeneity, and name 2 exceptions
multiple mutations on the same allele cause the same disease
exceptions: sickle cell, achondroplasia
explain locus heterogeneity, and name 4 examples
mutations in more than one gene cause the same disease (frequently involved in the same function or pathway)
Ex: breast/ovarian cancer, Fanconi anemia, xeroderma pigmentosum, Lynch syndrome
explain clinical heterogeneity, and name 3 examples
mutations in the same gene causes DIFFERENT phenotypes
Ex: FGFR3 (achondroplasia), MECP2 (Rett syndrome), RET (MEN or multiple endocrine neoplasia)
de novo mutations happen with people who have these 2 predispositions
- large genes with repeated motifs
- regions of methylated CpG islands
Ex: achondroplasia; thanatophoric dysplasia
neurofibramatosis type 1 is an example of ____, in which affected individuals within the same family show different features due to the presence of other genes, SNPs, or copy number variants
list 4 variations in recessive disease phenotypes
- common allele in a population (ex: sickle cell, G6PD deficiency, 21-hydroxylase
- founder effect (ex: Amish, Ashkenazi Jews, Finnish, Icelanders, Sephardim)
- gene expression levels (<50% causes abnormal phenotype)
- Consanguinity (biallelic state of rare mutations)
DNA methylation typically occurs on which base?
cytosine, in the 5' position
Note: generally occurs on CpG islands located in 5' ends of genes, found in ~70% of human genes. Hypermethylation corresponds with transcription repression
Histones have tails that stick out through DNA strands and are accessible to modifying proteins. What are 5 types of modification, from common to uncommon?
- acetylation (increase transcription) + deacetylation
- methylation (silence transcription)
acetylation of histones occur on ___ residues and are catalyzed by ___
lysine; HATs (histone acetyltransferase)
--> acetylation increases transcription, either by altering charge to separate histones from wrapped DNA, or creating a binding site for chromatin modifying enzymes and basal transcription machinery
Note: deacetylation is catalyzed by HDAC (histone deacetylase)
primary mechanisms we see related to epigenetics
DNA methylation, histone modification, silencing by ncRNA (noncoding)
ncRNA (noncoding RNA) is functional RNA that is not translated into protein - where are these found in the genome?
Translation: tRNA, rRNA, snoRNA, snRNA
Gene expression regulation: microRNA, siRNA, piRNA, long ncRNA
- between genes
- on the antisense DNA strand
discuss the inheritance pattern of imprinting
Imprinting is when only the allele from one parent is expressed - the "imprinted" gene is the INACTIVE one
Dominance of such alleles depends on WHICH PARENT PASSES IT ON, not on the allele itself
UPD (uniparental disomy) of an entire genome is possible (but does not result in live birth) - what structure forms from an ALL MATERNAL UPD, and what structure forms from an ALL PATERNAL UPD?
all maternal UPD: Ovarian teratoma, which is made up of disorganized EMBRYONIC STRUCTURES and no placenta
all paternal UPD: Hydatidiform mole of placenta, which is made up of disorganized PLACENTAL STRUCTURES (no fetus) and full of fluid-filled sacs
the 15q11.2 imprinting region can cause 2 different disorders depending on whether the mutation came from the mother or the father. Which disorders correlate with which parent?
Maternal inheritance - Angelman Syndrome
Paternal inheritance - Prader Willi syndrome
difference between regeneration and repair
regeneration is the replacement of damaged tissue with the exact same tissue type; repair is replacement of the tissue with a scar, classically known as "wound healing"
cells that are constantly regenerating, with stem cells constantly differentiating and entering the cell cycle
ex: skin (stem cell = stratum basale), lungs (stem cell = type 2 pneumocytes), bone marrow, GIT, GUT
Note: this cell type is the most likely to accrue MUTATIONS
cells that grow and stop dividing once they're done growing, sitting in G0 until prompted by external stimulus (e.g. injury) that causes them to re-enter the cell cycle
ex: liver, renal tubules, mesenchymal tissue (e.g. bone, cartilage, connective tissue, but NOT heart or skm)
cells that are unable to regenerate and will SCAR in response to injury (+3 examples)
ex: neurons, heart, skm
1) repair will be initiated in a LABILE/STABLE tissue if ___
2) the purpose of scar tissue is to provide tensile strength - define this
3) Tensile strength of the scar tissue will be no greater than ___% of regular tissue
1) repair is initiated if stem cell regenerative capacity is inhibited (ex: you get a cut to your skin that goes deep and destroys stem cells)
2) tensile strength = the ability to resist tension and stretching to tissue
(Note: scar tissue is not functional but adaptive - it cannot contract but it helps hold the tissue together)
4 overlapping phases in wound healing (general)
Phase 1: hemostatic (primary: platelet plug; secondary: activation of clotting cascade) - occurs almost immediately, platelets will degranulate
Phase 2: inflammatory (neutrophils 1-3 days; MPs 3-7 days)
Phase 3: proliferative (days-weeks)
Phase 4: remodeling/maturation (weeks-months)
3 growth factors released by platelet degranulation (during the hemostatic phase of wound healing)
PDGF, TGFbeta, FGF
Note: platelets also release vWF and fibrinogen for clotting and the hemostatic plug, and ADP and Ca2+ (needed for prothrombinase action)
During inflammation, vasodilation occurs at the ___ (vessel) and vascular permeability occurs at the ___ (vessel)
If a cardiac arrest patient's BP drops day 2 after a heart attack, the main cells causing necrosis/pericarditis are ___; if the patient starts to crash after a week in recovery, we know the main cells causing structural compromise are ___
neutrophils (arrive 1-3 days in); macrophages (arrive 3-7 days in)
granulation tissue is mostly made of Type ___ collagen, which is secreted by ___
Type III; fibroblasts
in which phase of wound healing would we see granulation tissue (pink, weak scarring that crumbles easily)?
Phase 3 - Proliferative phase
what happens during the remodeling phase of wound healing, and what molecules facilitate this?
weak Type III collagen is degraded by MMPs (metalloproteinases), and fibroblasts replace it with strong Type I collagen (which has 80% of the tensile strength of the original tissue)
Note: the majority of the scar's tensile strength is provided by collagen laid down in the first 3 months of wound healing
the most important growth factor in SCARRING (upregulates fibroblast proliferation and smooth muscle proliferation) - also plays a pathogenic role in formation of ATHEROSCLEROSIS
a ___ is excessive scar tissue confined to the borders of the initial wound (parallel arrangement of Type I collagen), whereas a ___ is a tough, irregularly shaped scar that extends outside the borders of the wound and contains lots of Type III collagen
hypertrophic scar; keloid
this growth factor is a potent ANTI-INFLAMMATORY agent (downregulates keratinocyte proliferation and the immune response once the body is done fighting the pathogen) - this is released by platelets initially, followed by leukocytes, MPs, fibroblasts, and keratinocytes
Note: this also stimulates fibroblast growth and angiogenesis in a healing wound
the most important angiogenic stimulator in developing embryos (and whose primary role is to stimulate angiogenesis to form collateral circulation in areas of blocked blood flow)
VEGF (vascular endothelial growth factor)
GF implicated in Wet Age-Related Macular Degeneration (and cancer pathogenesis)
VEGF (due to stimulation of too much angiogenesis in the retina, causing hemorrhage and vision loss)
GF implicated in achondroplasia due to its important role in epithelial cell regeneration and CARTILAGE DEVELOPMENT
FGF (fibroblast growth factor)
Note: FGF is the most responsible for keratinocyte proliferation
mutations in this growth factor (receptor) are most commonly implicated in cancer (especially lung cancer and breast cancer)
EGFR - EGF is a proto-oncogene important in cell proliferation, and EGFR is a target for inhibition by several cancer drugs (e.g. Cetuximab and Erlotinib)
ERBB1 (HER2/neu) overactivation is implicated in cancer, and the main target of the monoclonal Ab Trastuzumab
The most abundant type of connective tissue in the body, found directly beneath epithelial linings and serving as a reservoir of nutrient/ions for tissues
(the ___ is the term for this type of tissue when found lining mucosa)
loose connective tissue; lamina propria
connective tissue layer that serves as a major site of inflammatory/immune reactions since it is the first site bacteria and other pathogens reach after breaching the epithelium
what is the only cell type we find in dense connective tissue?
fibroblasts (which produce the ECM and maintain the ground substance)
dense irregular connective tissue are found in these tissues
- submucosa of the GIT
- deep (reticular) layer of the skin
Tendons, ligaments, and aponeuroses are made up of this type of connective tissue
deep regular connective tissue (fibers are organized in parallel fashion)
4 permanent resident cells of connective tissue
- mast cells
these cells express alpha-smooth muscle actin that contracts the edges of wounds closer together (important in granulation tissue)
myofibroblasts are important in ___ intention of wound healing
Note: primary = surgical/manual closure of a wound and tertiary = deliberately leaving wound open
tryptase is a biochemical marker of _____ (cell type) activity since they are specific to these cells
these residents of connective tissue synthesize granules containing inflammatory mediators e.g. histamine and heparin, which help vasodilation and Type I hypersensitivity reactions
what components make up ground substance (which is the viscous, gel-like substance occupying the space between cells and fibers of connective tissue)?
- GAGS (glycosaminoglycans)
- adhesive glycoproteins
where is hyaluronic acid found and what function does it serve?
it is a free large carbohydrate chain that found in the ECM that is hydrophilic and aggregates with proteins to make giant macromolecules - it acts as a shock absorber, lubricant, and regulates movement of molecules in the ECM
what proteins in ground substance gives it its viscous quality?
Sulfated GAGS (glycosaminoglycans), which are mucopolysaccharides - these GAGS are attached to core proteins to form proteoglycans, and all the sulfated groups give the molecule a HIGHLY NEGATIVE CHARGE, which attracts water into the ground substance
this disease is a mucopolysaccharidoses (lysosomal storage disorder with defect in an enzyme that breaks down GAGs) caused by a defect in alpha-L iduronidase enzyme
this disease is a mucopolysaccharidoses (lysosomal storage disorder with defect in an enzyme that breaks down GAGs) caused by a defect in iduronate sulfatase enzyme
this adhesive glycoprotein attaches cells to the ECM (binds integrins, Type IV collagen, heparin, and fibrin)
this adhesive glycoprotein binds Type IV collagen (primarily) and makes the FRAMEWORK of the basement membrane
the most abundant type of collagen
Type I collagen
these fibers are made up of heavily glycosylated Type III collagen and found in abundance in loose connective tissue to provide a support system to soft tissues
proteins that comprise elastic fibers
elastin and fibrillin
AA pattern making up collagen structure
Note: X and Y are usually Proline and Lysine (or hydroxyproline/hydroxylysine)
what cofactor is essential for the hydroxylation of Pro and Lys during collagen synthesis?
what cofactor is essential for the covalent lysine-hydroxylysine cross-linking of tropocollagen to form collagen fibrils? What enzyme catalyzes this cross-linking?
enzyme: lysyl oxidase
disease caused by a mutated ATP7A protein, which is essential in ___ absorption and metabolism
Menkes Disease -- copper absorption
disease caused by autoimmune attack on the alpha-3 chain of Type IV collagen, which is especially important in the basement membrane of the lungs and kidneys - this disease presents with renal failure and bloody urine/coughing
disease caused by mutation in Type IV collagen that affects the basement membrane of the inner ear, eyes, and kidneys, resulting in hearing loss, blindness, and renal failure
type ___ collagen is found in the basement membrane
type ___ collagen is found in blood vessels
type ___ collagen is found in cartilage
Type ___ collagen is found in bone
patients with this disease presents with blue sclera and hearing loss (what is the main protein affected?)
Osteogenesis Imperfecta - Type I Collagen
patients with this disease spectrum of mostly autosomal-dominant disorders have defective collagen synthesis of skin, joints, and blood vessels - in addition, what mutation causes the classical form, and what mutation causes the most severe form?
Classical form: defect in Type V collagen (associated with joint hypermobility and hyperlax skin)
Severe form: defect in Type III collagen, prone to vascular prolapse, organ rupture, aneurysms, etc.
breakdown of this fiber causes emphysema due to lost elasticity in the lung (less ability to expand = more difficulty breathing)
this glycoprotein microfibril is essential for the ASSEMBLY (and scaffolding) of elastin fibers
this disease presents with lens subluxation (lens shifted out of place) and extremely long limbs/features due to a loss in ___ (protein)
Marfan syndrome; fibrillin
most connective tissue diseases have this mode of inheritance
what disease should you suspect if you encounter unexplained emphysema and cirrhosis together?
THIS SET IS OFTEN IN FOLDERS WITH...
Foundations 2 Week 3: Adaptive Immunity
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Foundations 2 Week 5: Cancer drugs and counseling
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