Term
| What disease manifests as asymmetric muscle contraction often arising from mutations in the protein Titin? |
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Definition
Muscular Dystrophy.
Remember, Titin links Myosin to Z-lines, acting as a tensile spring during contraction. |
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Term
| What issue is cell devision might result in the absence of GTP? |
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Definition
Microtubule polymerization depends on GTP-bound tubulin.
Kinetochore microtubule spindles can't be produced to "fish" for chromosomes in the absence of GTP. This could cause asymmetric divisions and monosomy/trisomys.
** Actin uses ATP and Microtubules use GTP ** |
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Term
| A defect in this molecule could cause abnormal migration of centrioles to opposite cellular poles. |
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Definition
Kinesin
Remember, Kinesin is a (-) end motor that takes cargo to the outsides of the cell. |
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Term
| What could a deficiency in Netrin and/or Eprhin proteins have to do with abnormal embryonic neural migration? |
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Definition
Intermediate targets secrete netrins, which attract growing axons in the developing embryo.
Ephrins are (-) regulators that bind RTK Ephrin receptors on growth cones. |
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Term
A patient presents with an absent Aurbach's plexus.
What disease are you concerned that they have?
How would you test for it? |
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Definition
1) Hirshprung's
2) Mutations in RET receptors (binds GDNF). They cause abnormal neural crest migration into the intestine. |
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Term
| Why might mutations in Selectin genes be of concern in terms of endothelial infection? |
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Definition
Selectins are carbohydrate and calcium-dependent surface receptors that are expressed in inflamed tissues and attract lymphocytes.
After binding to integrins, lymphocytes enter endothelial cells. |
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Term
1) What does the progression of melanomas have to do with integrins and cadherins?
2) How can E-caherin be used to treat them? |
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Definition
After initial radial growth, vertical growth of tumors is associated with changes in these surface molecules that enable them to interact with tissues where they can mature.
2) In a melanoma, melanocytes are no longer restricted by keratinocyte fibers as they are normally.
E-cadheren retards cell growth by conferring a keratinocyte-dependent normal melanocytic phenotype |
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Term
| A patient presents with aberrant blistering and you discover a mutation in the desmogelin-3 gene. What disease it this and how does it occur? |
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Definition
Pemphigus Vulgaris- Desmosome issue that causes abnormal cell-cell attachments. Desmogleins project into the intercellular space and enable adhesion.
Remember, keratins are important in desmosomes and are bound by plakophilin and desmoplakin. Keratins also bind to hemidesmosomes which protect epithelia against shearing forces. |
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Term
| A patient presents with hypomagnesemia, hypercalciuria and nephrocacinosis in the loop of Henle. What might be going on? |
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Definition
| Mutations in Claudin-16, an integral membrane protein that interacts with the actin cytoskeleton via ZO-1, ZO-2 and ZO-3 (peripheral membrane proteins) to allow the selective passage of anions and cations such as magnesium and calcium |
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Term
| Why might inflammation of umbrella cells in the uroepithelium be of clinical importance? |
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Definition
| Transitional cells line renal pelvis, ureter and bladder and allow stretching of these tissues when fluids move through them. |
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Term
After performing gene-linkage analysis, you discover a history of mutations in the plakaglobin (y-catenin) gene family.
Where might these mutations cause issues and what is the associated disease called? |
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Definition
1) Naxos Disease causing abnormal tissue architecture in the heart, skin and hair follicles.
2) Y-catenins are the cytoplasmic components that associate with Cadherens that form desmosomes and adherens junctions. |
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Term
What happens when Connexin-50 is mutated?
What about Connexin-32
Connexin-26 |
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Definition
Gap Junction Diseases
1) Cataracts in lens
2) Charcot-Marie-Tooth disease with motor and sensory defects
3) Deafness |
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Term
| How can supravalvular aortic stenosis arise? |
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Definition
Issues with lysine cross-linking via lysyl oxidase (Cu, Fe and Vit-C dependent) impairs elastin assembly.
Hypertrophy and hyperplasia result and can lead to MI |
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Term
What are the clinical implications of deficiencies in the following ECM components?
1) Fibronectin
2) Laminin-1
3) Laminin-2 |
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Definition
1) Defective vascular development
2) Basement membrane dies off and pre-implantation death occurs (same for beta- 1 integrin and dystroglycan receptors)
3) Congenital muscular dystrophy |
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Term
| Which ECM components are critical to protect again stomach erosion by HCl? |
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Definition
| Mucins bound to Sialic Acid (- charge) |
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Term
| Why do auto-antibodies against collage alpha3 (IV) cause issues? |
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Definition
This is Goodpasture Syndrome
Basement membrane is made from collagen 4 and these antibodies breakdown the BM. |
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Term
| What potential issues could arise from mutations in the lysyl oxidase enzyme? |
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Definition
1) Problems with lysine cross-linking in elastin fiber assembly (supravalvular aortic stenosis)
2) Problems with fibrillar collagen crosslinking at N and C terminal ends of triple helices |
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Term
| What ECM components are involved in arthritis development? |
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Definition
Proteoglycans such as aggrecan usually attract sodium and water to their negatively charged acidic groups (such as hyaluronic acid in aggrecan), which resists compression.
When these are absent, there is no padding. |
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Term
| What disease arises from a single AA switch of Glycine in Collagen 1? |
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Definition
Osteogenesis imperfecta (OI)
Impaired collagen triple helix formation because glycine cannot hydrogen bond and promote helix formation.
** This can also arise from defective cleavage sites in N- or C- terminal pro-peptides or mutations in the C and N-terminal peptidases that expose collagen ends for multi-fiber assembly** |
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Term
While attempting to put a patient under anesthesia for surgery (using halothane and succinylcholine), you notice extreme muscle rigidity and a hypermetabolic state with increased oxygen consumption and hyepercarbia.
What condition is this, how does it arise and how can it be treated? |
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Definition
1) Malignant Hyperthermia (MH)
2) Genetic defect in Ryanodine receptor
3) Dantrolene intravenously acts directly on RYR (must do it quick or 80% die!) |
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Term
| Why might treatment with botox use lead to muscle atrophy? |
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Definition
- Botox presents presynaptic Ach release and prevents contraction.
- This change can be perceived by muscle cells as "denervation" and can cause them to atrophy. |
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Term
For each aspect of the NMJ, give an example of a drug that can target it.
1) Ach receptors (nicotinic)
2) Presynaptic Ach release
3) Post-synaptic, depolarizing NMJ blocker
4) Post-synaptic, non-depolarizatin NMJ blocker (block Ach binding)
5) Inhibit AchE |
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Definition
1) alpha-Bungarotoxin
2) Botox and TTX
3) Succinylcholine (bungarotixin "for doctors")
4) Curare, Rocurorium
5) Organophosphates |
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Term
| How would you treat someone following acute organophosphate exposure? |
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Definition
Use Atropine to inhibit the Ach receptor (muscarinic) and then reactivate the AchE enzyme with Pralidoxime.
Remember, organophosphates inhibit AchE, which prevents Ach reuptake and degradation and causes prolonged contractions and paralysis. |
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Term
| How do you treat Myasthenia gravis (can't contract!). |
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Definition
| AchE inhibitors that act like organophosphates |
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Term
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Definition
- After death, muscles stay contracted because no ATP is left to release myosin from actin.
- Muscle remains contracted until contractile proteins degenerate with time |
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Term
| Why might a mutation in the gene encoding Caspase 3 be of concern in pregnant women? |
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Definition
Caspase 3 regulates cell death of contractile elements (myosin and actin) during pregnancy, thereby maintaining uterine quiescence during pregnancy.
Mutations might cause abnormal contractions and damage to the fetus. |
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Term
| How can Teriparatide be used clinically? |
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Definition
-Only drug to build bone (N-terminal peptide of PTH)!
- Stimulates osteoclasts, which has net effect of stimulating osteoblasts to lay down collagen 1 and produce alkaline phosphatase.
- After 6 months, growth shifts towards absorption |
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Term
| Why use a SERM to treat osteoporosis? |
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Definition
| - Estrogen receptor activation promotes apoptosis of osteoclasts, presumably through TGF-B. This stunts bone resorption (used secondarily to Bisphosphonates and can cause thromboembolisms) |
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Term
| Why are metaphyseal veins in children so susceptible to osteomyelitis? |
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Definition
| Since bones are vascularized, they are susceptible to blood-borne infection (hematogeneous), as well as contiguous infections through the periosteum. |
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Term
| Explain the disproportionate damage to spongey bone vs. compact bone seen in osteoporosis. |
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Definition
| - Spongey bone is turned over 25% each year vs. 3-4% for compact bone. Since there is decreased growth in osteoporosis, you lose spongey bone faster! |
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Term
| Why might a mutation in the gene encoding osteoprotegrin be of clinical concern? |
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Definition
Osteoprotegrin blocks RANK ligand, preventing abberant osteoclast maturation and bone resorption when plasma calcium is high.
Mutations in this gene could cause aberrant bone resorption and osteoporosis! |
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Term
1) What would you use the Bisphonate, Alendronate, to treat?
2) What are some alternatives? |
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Definition
Bisphonates such as Alendronate are used to treat osteoporosis because they bind calcium hydroxyapatite and decrease bone resorption by clocking function and survival of osteoclasts w/o affecting their formation.
Growth slows after 1 year and can necrosis can occur after 5 years!
2) SERMS, Tariparatide (growth), Calcitonin (primarily in post-menopausal women) |
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Term
| What disease is identified by the presence of multiple cement lines in bone and what does this mean? |
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Definition
Paget's Disease
Too many cement lines indicate that too much bone turnover is occuring |
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Term
| Why does ALS relate to a SOD-1 mutation? |
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Definition
| SOD-1 is the "fuel" supply for anterograde transport of mitochondria and retro/anterograde vesicular transport. |
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Term
| In which vessels is an Aortic Aneurism of concern? |
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Definition
| The Aorta is a "Elastic Artery," meaning that it has a thick tunica media with elastin throughout. |
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Term
| In which vessels is Arteriosclerosis of concern? |
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Definition
| Muscular Arteries, which possess thick tunica medias with elastin restricted to the internal and external elastic lamellae, as well as surrounding the endothelial cells of the tunica intima lumen. |
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Term
| Why would a mutation in the gene encoding prostacyclin be of clinical concern? |
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Definition
Prostacyclin, along with NO, control vasodilation of arterioles and regulate the myogenic response of blood flow into capillary beds.
Remember, Endothelin is responsible for vasoconstriction here. |
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Term
| How is blood entry into capillaries regulated by pre-cappilary sphincters? |
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Definition
| Adenosine and low O2 opens them. |
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Term
| You notice that patient is not extravasating adequate white blood cell volumes from the bloodstream into connective tissue. What vessels may not be working adequately? |
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Definition
These are Post-capillary venules!
Remember, venues, like veins, have a larger adventitia than media and only a single, incomplete layer of smooth muscle in the media. |
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Term
| Why would you be concerned about a Kwashiorker patient suffering edema? |
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Definition
| Lack of plasma proteins decreases osmotic force in capillaries, allowing water to drain out. This is also seen in burn victims and inadequate lymph drainage. |
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Term
| What are 2 therapeutic methods for enhancing adult angiogenesis? |
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Definition
1) Treat with Bone marrow injections to increase EPC count (can differentiate into hemangioblasts via VEGF signaling, which can turn into blood and vessel cells.
2) Treat with local and/or systemic VEGF via gene therapy in areas of impaired vascularity.
ISSUE- can cause increased permeability and edema! |
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Term
| What are 4 therapeutic methods for inhibiting Angiogensis? |
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Definition
1) Remove VEGF signaling via neutralizing antibody (Bevacizumab/Avistan)
2) Inhibit VEGF receptor signaling with RTK inhibitors or by blocking receptor binding with an antibody.
3) ECM breakdown product mimetics
4) Natural MMP inhibitor Neovastat (remember, MMPs breakdown ECM components). |
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Term
| Which neutralizing antibody to VEGF is used to treat colorectal cancer? |
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Definition
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Term
Which multi-target RTK inhibitor is used to treat renal cell carcinoma?
What about for advanced kidney cancer and GI stromal tumors? |
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Definition
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Term
| Which Thalidomide anlog reduces VEGF in the treatment of myelodystplastic syndrome? |
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Definition
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Term
| Which EGF tyrosine kinase inhibitor is used to treat lung cancer? |
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Definition
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