Pathophysiology Questions

1. The figure to the right illustrates the effect of different mutations on the 150 Vehicle Control relative activity of a receptor for a small peptide hormone (ligand). Receptor Liganc Specifically, HEK239 cells were transfected with either the normal (WT) or 100 each of five mutant receptors and the relative activity was measured in the presence or absence (vehicle control) of the receptor’s ligand using cAMP 50 production as an indicator.

a. Based on these data what can youinfer about the state of this receptor under basal (resting) conditions? How do you know? WT M JutantReceptors

b. Let’s suppose this receptor is normally expressed in the pyramidal tract, a group of nerve fibers needed for voluntary motor movement; what could be a pathophysiological outcome if an individual harbors a receptor with any of the five mutations illustrated above? Be specific.

c. Do you think the pathophysiological outcome would be the same if the person harbored a gain-of-function mutation? Why or why not?

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2. Altered gene function and disruption of cellular signaling pathways, both intra- and intercellular, are underlying mechanisms for a myriad of pathological conditions.

a. What is the significance of oxidative stress for the genetic basis of disease?

b. Could impaired and/or altered rates of protein turnover disrupt cellular signaling pathways? How?

c. Is DNA damage relevant to cell signaling? In other words, could DNA damage disrupt normal cell signaling? How?

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3. The figure to the right illustrates intracellular pH and ATP levels under each of two 7.2 the conditions denoted by the white (Time 0 28 min & 56 84 min) and shaded 7.0 (Time 28 56 min) areas.

a. What is a likely explanation for the observed changes? 6.6 6.4

b. What are the biochemical mechanisms responsible for each of these effects 6.2 (i.e., altered pH and ATP)? 6.0

c. Would anything other than intracellular levels of pH and ATP be affected by 12 this treatment? If yes, provide an example and a (plausible) biochemical 10 mechanism responsible. d. Suppose the treatment noted by the shaded area was ten times longer, do 60000 you suppose the outcome for the cell would be the same? Why or why not? Time (min)

4. A mutation was introduced into an experimental mouse model that resulted in the heart morphology seen to the right. The heart on the left is from the normal (wild-type) mouse, while the heart on the right is from the mutant mouse. Clearly, the heart to the right is abnormally large.

a. How could you determine whether this is due to a hyperplastic or a hypertrophic condition?

b. Propose a mechanism whereby the mutation induces either: i. Cellular hyperplasia ii. Cellular hypertrophy Note: specific condition is not needed; a general explanation will suffice

c. Propose a mechanism that could result in cardiac atrophy (Hint:Look to the stars). Why does it occur?

5. The figure to the right illustrates three things: (1) FasL(200 ug/inL) the effect of FasL on the number (% Control) of 100 – 25 cells present in each of two cancer cell lines (RD C-8 80 60 FasL and Rh1) bar graph to the left. The black bars 60 45 Fas – represent vehicle treated cells; the striped bars 40 DRS — represent FasL treated cells. (2) The number of cells present in each of these same two cell lines 20 in response to increasing doses of TRAIL line to 100 graph. The black line represents RD cells while RD Rh1 TRAIL (ng/ml) the grey line represents Rh1 cells. (3) The amount of RNA present for Caspase 8 proenzyme (C-8), Fas ligand (FasL), Fas and death receptor 5 (DR5) inset.

a. Based on these data, which process most likely accounts for the loss of Rh1 cells under each treatment regimen (Fasl and TRAIL exposure) and the loss of RD cells in response to TRAIL?

b. Propose a mechanism to explain the difference in the cellular response to FasL and TRAIL in RD versus Rh1 cells. That is, why is the number of Rh1 cells lower in the presence of both FasL and TRAIL (be specific)?

EXTRA CREDIT Bill is 45 yo and presents to the ER at Mass General with persistent red patches on both upper thighs which itch and are mildly painful. He says he noticed them about two weeks before and that they have worsened with time. His body temperature and vital signs are normal. Examination of the affected areas is consistent with sunburn, but it is the winter and Bill does not use tanning beds. While taking his history, the admitting nurse notes Bill recently begun working for a company that services and maintains medical instruments. This includes scintillation and gamma counters which are used by diagnostic labs to make radioisotope-based measures. Consequently, they require calibration with an I-129 source with a known level of activity. Histological examination of scrapings from each lesion reveals thickening of the epidermis and inflammatory infiltrates consistent with first-to-second degree burns; burn depth is significantly deeper on the right thigh.

What do you think has caused these lesions? What may account for the discrepancy in burn depth among the lesions?