Transcript APPH 6211 Systems Physiology I: Cellular mechanisms of

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
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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
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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
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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
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Nucleus
Endoplasmic reticulum
Golgi apparatus
Mitochondria
• Protein complexes
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ORC
Transcription complexes
Ribosome
Proteasome
Information coding model
• Gene
– Intron/exon
– Promoter
– Remote regulatory regions
• RNA
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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
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Modular domains
Structure/shape
Chemical properties
Co-translational modifications
• Function
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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
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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
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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