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APPH 6211 Systems Physiology I: Cellular mechanisms of plasticity • Text: Cell Biology Updated Edition. T.D. Pollard, & W.C. Earnshaw, eds Elsevier (2004) ISBN 1-4160-23887 Saunders (2007) ISBN 978-1416022558 • Instructor: Tom Burkholder 555/575 14th St, 1309F, 4-1029, [email protected] • On-campus hour: • Exam: (Tentative) Sep 19, Oct 10, Nov 7, Dec 12 • • Online Syllabus & Readings: http://www.ap.gatech.edu/Burkholder/6211/ Other references W. Boron, E.L. Boulpaep Medical Physiology B. Alberts et al. Molecular Biology of the Cell http://www.ncbi.nlm.nih.gov/books/NBK21054/ D. Silverthorn Human Physiology Policies • • • • Honor code Closed-book exams No make-up exams Class attendance optional Special Challenges • Engineers – Be prepared to work – APPH/BIOL 3751 BIOL 4446 BMED 3160 • • • • Biochemistry Generic cellular mechanisms Specific physiological applications Project Cellular processes as dynamical systems • Plant – performs some physiological function • Controller – changes rate/efficiency of plant • Sensor – monitors effectiveness of plant Controller Plant Sensor • Homeostasis – tendency to maintain an internal state • Stability of the dynamical system Physiological Themes • Homeostasis – Negative feedback - stable – Steady-state condition (usually non-equilibrium) – Sensors & controls • Excitability – Positive feedback - unstable – Energy storage & release – Communication • Plasticity – Change that brings about homeostasis – Temporal hierarchy Cell structure • Cytoplasm • Organelles – – – – Nucleus Endoplasmic reticulum Golgi apparatus Mitochondria • Protein complexes – – – – ORC Transcription complexes Ribosome Proteasome Information coding model • Gene – Intron/exon – Promoter – Remote regulatory regions • RNA – – – – m/t/r Transcription Alternative splicing Translational regulation • Protein Central dogma Flippantly coined by Francis Crick in the 1950s, which he and Watson would come to despise for its misinterpretation. They meant it for the idea that information flows from nucleic acids to proteins and never backwards. Protein • Structure – – – – Modular domains Structure/shape Chemical properties Co-translational modifications • Function – – – – Structure Synthesis Transport Post-translational modification Model systems • Posture (BB 9, 12-14) – Muscle force generation – Neural regulation • Blood homeostasis (BB 32-39) – Glomerular filtration – Hormonal regulation Blood homeostasis • Volume/pressue homeostasis • Composition homeostasis • Kidney function – Osmotic regulation – Hormonal regulation – Neural regulation Kidney function • Free fluid transfer from capillaries to Bowman’s capsule – 70 nm epithelial cell fenestrations – Mechanical filter only • Fluid reabsorption in proximal tubule – Osmotically powered by NaCl transport – Also HCO3-, Ca2+, etc • Osmotic balancing in Loop of Henle • Final polishing in distal tubule/collecting duct Control of glomerular filtration • Fluid mechanics – Physical pressure in glomerular capillaries – Osmotic pressure – 125 ml/min! • Myogenic response • Tubuloglomerular feedback Glomerular Blood flow Distal Tubule Na+ Fluid removal Control of proximal tubule reabsorption • Proximal tubule – Na+ driven cotransporters lumenal – Active transport of Na+ basolateral • Glomerulotubular balance – Reabsorption of constant Na+ fraction – Dialysis of filtrate against remaining fluid • Hormonal regulation (hypothalamus) – Endogenous ATPase inhibitor – Blocks NaK Na+ reabsorption Endogenous ATPase inhib Systemic [Na+] Neural control of filtration • Collecting duct – Final polishing of urine – 2-3% Na+ reabsorption • Sympathetic NS – – – – – Norepinepherine Vasoconstriction reduces GFR Renin-Aldosterone stimulation Increases Na+ reabsorption Thirst Na+ reabsorption Circulating volume Aldosterone Cellular aspects of blood homeostasis • Kidney – Hemodynamics – Channel kinetics – Pump activity • Chemical sensors – Monitoring of electrolytes, organic solutes – Local control • Sympathetic nervous system – Monitoring of “global” parameters – Signal processing – Coordinated control Posture • Maintain body configuration – Intrinsic instability – Extrinsic perturbation • Control loops CoM – Intrinsic (muscle) – Peripheral (spine) – Central (brainstem & cortex) Inverted pendulum model of posture Intrinsic control of posture • Sarcomere – – – – Interdigitating filament matrices Crossbridge Elasticity Viscosity Sarcomere structure • Control derived from autonomous behavior Tension step response Crossbridge binding Filament overlap a=F/m Peripheral control of posture • Muscle spindle – Specialized muscle fibers – Sensory afferent – Length & velocity sensor • Motor neuron – Controls many fibers – Stimulated by spindle afferent • Control derived from communication Motor neuron between cells a=F/m recruitment Spindle firing Central control of posture • Vestibular system – Semicircular canals – angular acceleration – Otolith organs – linear acceleration • Cerebellum – Integrates multiple sensory systems – Forms whole body model – Organizes response • Control derived from information outside the immediate effector Cellular aspects of postural control • Muscle – Regulation of force generation – ATP homeostasis – Force capacity homeostasis • Spindle – Monitoring of physical stimuli – Rapid communication • Motor neuron – Signal processing – Rapid communication – Learning