Open-ended problems with calculation related to pharmacogenomics (including biology, cell signaling)

1) Howie Mandel was diagnosed with type I (insulin – dependent) diabetes mellitus when he was 12 years old. At the time of his diagnosis, Howie was in middle school. He was an excellent student and had many friends. At a sleepover party, the unimaginable happened: Howie wed his sleeping bag! He might not have told his parents except he was worried about other symptoms he was having. He was constantly thirsty and urinating every 30 to 40 minutes. Furthermore, despite a voracious appetite, he seemed to be losing weight; all of his pants had become loose in the waist. Howie’s parents panicked because they knew that these were classic symptoms of diabetes mellitus. They took Howie to see his pediatrician immediately. The pediatrician performed a physical examination and ordered laboratory tests (see Table 1). Table 1 Height 5 ft, 3 inches Weight 100 pounds (decrease 5 pounds from his annual checkup two months earlier) Blood pressure 90/55 (lying down), 75/45 (standing up) Fasting plasma glucose 320 mg/dL (normal equal 70 –110 mg/dL) Plasma ketones 1+ (normal =0 or none) Urinary glucose 4+ (normal =0 or none) Urinary ketones 2+ (normal =0 or none) a) How did insulin deficiency lead to an increase in Howie’s blood glucose concentration? b) How did insulin deficiency lead to the finding of ketones in Howie’s blood and urine? c) Why did Howie have glucose in his urine (glucosuria)? d) Why did Howie have increased urine production (polyuria)? Why was he drinking so much (polydipsia)? e) Why was Howie’s blood pressure lower than normal? Why did it decrease further when he stood up? f) Howie takes his insulin by subcutaneous injection – why can’t he take insulin orally? 2 g) The endocrinologist and closely monitors Howie’s renal function. What is the major enough nephrologic complication of type I diabetes mellitus? 2) Suppose the circulating concentration of hormone is 10-10 M and the Kd for binding to its receptor is 10-8 M. What faction of the receptors will have hormone bound? If a meaning full physiological response occurs when 50% of the receptors have bound a hormone molecule, how much will the concentration of hormone have to rise to elicit a response? We assume that the Law of Mass Action holds. 3) A new pharmaceutical agent (PA) is developed which, unknown to everyone, binds to the carrier protein (CP) in the system diagrammed below (Figure 1) and enhances the binding of H. What would be the effect of injecting PA on: 1. the immediate action of H on its target cell; and 2. the biological half-life of H (i.e., the time necessary for the concentration of H to reach 1/2 its original concentration assuming no new secretion)? H X Endocrine Gland Target Tissue Liver Metabolism/ Kidney Excretion (+) (+) (-) (-) (-) Carrier Protein Stimulus Figure 1 BMES 604 – Assignment 3 3 3 4) Lauren and Tim Patterson recently had their second child, a girl they named Paula Carter. A day after delivery, the pediatricians told the Patersons that Paula Carter ‘s clitoris was enlarged. The pediatrician ordered a chromosomal evaluation, which confirmed an XX (female) genotype. Other tests showed that the child had ovaries, uterus, and no testes. Table 2 gives the results of laboratory tests. Table 2 Blood glucose 70 mg/dL (normal fasting,70-100 mg/dL) Serum cortisol low – normal Serum ACTH increased 17-ketosteriod excretion increased The consulting pediatric endocrinologist made a diagnosis of congenital adrenal hyperplasia secondary to 21β-hydroxylase deficiency. It was recommended that Paula Carter receive hormone replacement therapy and that she undergo surgery to reduce the size of her clitoris. a) Using your knowledge of the biosynthetic pathways of the adrenal cortex, predict the consequences of21β-hydroxylase deficiency. Which adrenocortical hormones will be deficient? Which hormones will be produced in excess? b) What are the expected physiological consequences of the hormonal deficiencies you predicted about? c) Why was Paul Carter’s serum adrenocorticotropic hormone – ACTH – level increased? d) Paul Carter’s blood glucose and certain cortisol levels were both low – normal. Why weren’t these values more obviously abnormal? e) What was the significance of her increased urinary excretion of 17-keto steroids? f) Why was Paul Carter’s clitoris enlarged at birth? g) Did Paula have partial or complete deficiency of 21βhydroxylase? h) What hormone replacement therapy did she receive? 4 i) In terms of her development, what might have happened if Paula Carter’s condition had not been diagnosed and she did not receive hormone replacement therapy? 5) Consider a hypothetical second messenger system where G proteins perform their standard tasks and a second message is generated by enzyme X. Predict the consequences on chemical signaling of a pharmaceutical agent which effects the G protein or enzyme X according to Table 3. Assume standard Michaelis – Menton enzyme kinetics (Briggs Haldane modification). 

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