Systems endocrinology
-
Upload
jaunidhenakan -
Category
Science
-
view
176 -
download
7
Transcript of Systems endocrinology
SYSTEMS BIOLOGY @ SYSTEMS MEDICINESYSTEMS ENDOCRINOLOGYJ. W. DIETRICH
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 2
Conflict of Interest:
Patent application “System and method for deriving parameters for homeostatic feedback control of an individual” by S. L. Goede, J. W. Dietrichand Melvin K. S. Leow (A*STAR), WO/2014/088516, PCT/SG2013/000515
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 3
Gerhard Mercator (1512 – 1594)
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 4
Gerhard Mercator (1512 – 1594)
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 5
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 6
Mercator Projection
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 7
Hammer-Aitov Projection
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 8
Goode homolosine Projection
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 9
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 10
Metabolic Maps
G. Michal (1965, 1999, 2012, 2014) Biochemical Pathways
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 11
Metabolic Maps
G. Michal (1965, 1999, 2012, 2014) Biochemical Pathways
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 12
Processing Structures
Mittelstaedt H. Triple-loop model of path control by head direction and place cells. Biological Cybernetics. 2000 Sep;83(3):261-70. PMID 11007300.
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 13
Correlation Networks
Gie
bels
tein
J e
t al..
The
pro
teom
ic s
igna
ture
of i
nsul
in-r
esis
tant
hu
man
ske
leta
l mus
cle
reve
als
incr
ease
d gl
ycol
ytic
and
dec
reas
ed
mito
chon
dria
l enz
ymes
. Dia
beto
logi
a. 2
012
Apr
;55(
4):1
114-
27.
doi:
10.1
007/
s001
25-0
12-2
456-
x. P
MID
222
8216
2.
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 14
Interaction Networks
www.bsse.ethz.ch
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 15
Metabolic Flux Analysis
wormbook.org
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 16
The Concept of Homeostasis
La fixité du milieu intérieur est la conditionde la vie libre, indépendante.
Claude Bernard (1813 – 1878)
The coordinated physiological processes which maintain most of the steady states in the organism are so complex and so peculiar to living beings … that I have suggested a special designation for these states, homeostasis. … It means a condition--a condition which may vary, but which is relatively constant.
Walter B. Cannon (1871 – 1945)
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 17
The Concept of Homeostasis
Regelungstechnik. Die technische Aufgabe und ihre wirtschaftliche, sozialpolitische und kulturpolitische Auswirkung.
Hermann Schmidt (1894 – 1968)
Cerebral Inhibition Meeting 1942Macy-Conferences 1946 – 1953
Cybernetics Group andNorbert Wiener
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 18
Homeostasis in Endocrinology
Moore, C.R. & Price, D. (1930) The question of sex hormone antagonism. Proceedings of the Society for Experimental Biology and Medicine , 28, 38–40.
Moore, C.R. & Price, D. (1932) Gonadal hormone functions, and the reciprocal influence between gonads and hypophysis with its bearing on the problem of sex hormone antagonism. American Journal of Anatomy, 50, 13–67.
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 19
Hohlweg, W. & Junkmann, K. (1932) Die hormonal-nervöse Regulierung des Hypophysenvorderlappens. Klinische Wochenschrift, 11, 321–323
Homeostasis in Endocrinology
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 20
Discovery of Thyroid Homeostasis
Roy Graham Hoskins(1880–1964)
Edwin Bennett Astwood(1909–1976)
E. B. Astwood (1936) Treatment of Hyperthyroidism with Thiourea and Thiouracil.JAMA 122;2: 78–81
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 21
Discovery of Thyroid Homeostasis
Roy Graham Hoskins(1880–1964)
Edwin Bennett Astwood(1909–1976)
R. G. Hoskins (1949) The Thyroid-Pituitary Apparatus as a Servo (Feed-Back) Mechanism. JCEM 9: 1429–31
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 22
Publications with PubMed search term "pituitary AND thyroid AND (feedback OR homeostasis)"
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 23
Early models
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 24
Early models
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 25
Early models
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 26
Early models
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 27
Early models
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 28
Modelling Techniques
Building Bricks for “Parametrically Isomorphic” Models
Elimination and Distribution
Michaelis-Menten Kinetics
Non-competitive Inhibition
Plasma Protein Binding
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 29
Modelling Techniques
Building Bricks for “Parametrically Isomorphic” Models
Elimination and Distribution
Michaelis-Menten Kinetics
Non-competitive Inhibition
Plasma Protein Binding
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 30
Modelling Techniques
Building Bricks for “Parametrically Isomorphic” Models
Elimination and Distribution
Michaelis-Menten Kinetics
Non-competitive Inhibition
Plasma Protein Binding
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 31
Modelling Techniques
Building Bricks for “Parametrically Isomorphic” Models
Elimination and Distribution
Michaelis-Menten Kinetics
Non-competitive Inhibition
Plasma Protein Binding
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 32
Modelling Techniques
Building Bricks for “Parametrically Isomorphic” Models
Elimination and Distribution
Michaelis-Menten Kinetics
Non-competitive Inhibition
Plasma Protein Binding
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 33
Modelling Techniques
Building Bricks for “Parametrically Isomorphic” Models
Elimination and Distribution
Michaelis-Menten Kinetics
Non-competitive Inhibition
Plasma Protein Binding
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 34
MiMe-NoCoDI Platform
For k parallel loops:
Dietrich JW, Boehm, BO (2006) Equilibrium behaviour of feedback-coupled physiological saturation kinetics. Cybernetics and Systems 2006. 269-74. DOI: 10.13140/2.1.2400.2568
Equifinal solution:
Interative equation:
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 35
MiMe-NoCoDI Platform
Dietrich JW, Boehm, BO (2006) Equilibrium behaviour of feedback-coupled physiological saturation kinetics. Cybernetics and Systems 2006. 269-74. DOI: 10.13140/2.1.2400.2568
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 36
MiMe-NoCoDI Thyroid Model
Midgley, Hoermann,, Larisch and Dietrich (2013) Physiological states and functional
relation between thyrotropin and free thyroxine in thyroid health and disease: in
vivo and in silico data suggest a hierarchical model Journal of Clinical Pathology 66;4:
335–42
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 37
Midgley, Hoermann,, Larisch and Dietrich (2013) Physiological states and functional
relation between thyrotropin and free thyroxine in thyroid health and disease: in
vivo and in silico data suggest a hierarchical model Journal of Clinical Pathology 66;4:
335–42
MiMe-NoCoDI Thyroid Model
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 38
MiMe-NoCoDI Model
Dietrich JW, Landgrafe G, Fotiadou EH. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis. J Thyroid Res. 2012;2012:351864. doi: 10.1155/2012/351864. PMID 23365787
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 39
MiMe-NoCoDI Model
Dietrich JW, Landgrafe G, Fotiadou EH. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis. J Thyroid Res. 2012;2012:351864. doi: 10.1155/2012/351864. PMID 23365787
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 40
MiMe-NoCoDI Model
Dietrich JW, Landgrafe G, Fotiadou EH. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis. J Thyroid Res. 2012;2012:351864. doi: 10.1155/2012/351864. PMID 23365787
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 41
Pulsatile TSH Secretion
Greenspan SL, Klibanski A, Schoenfeld D, Ridgway EC. Pulsatile secretion ofthyrotropin in man. J Clin Endocrinol Metab. 1986 Sep;63(3):661-8. PMID3734036.
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 42
Pulsatile TSH Secretion
J. W. Dietrich, A. Tesche, C. R. Pickardt, and U. Mitzdorf,“Thyrotropic feedback control: evidence for an additionalultrashort feedback loop from fractal analysis,” Cyberneticsand Systems, vol. 35, no. 4, pp. 315–331, 2004.
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 43
T3 Dissociation
Hoermann, Midgley, Larisch and Dietrich,Is Pituitary TSH and adequate measure of
thyroid hormone-controlled homeostasisduring thyroxine treatment? EJE 2013: 168
271–80
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 44
NTIS / TACITUS
Dietrich, J. W., G. Landgrafe, E. H. Fotiadou (2012). TSH and thyrotropic agonists: Key actors in thyroid homeostasis. Journal of Thyroid Research, vol. 2012,
Article ID 351864, 29 pages, 2012. doi:10.1155/2012/351864
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 45
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 46
Midgley, Hoermann,, Larisch and Dietrich (2013) Physiological states and functional
relation between thyrotropin and free thyroxine in thyroid health and disease: in
vivo and in silico data suggest a hierarchical model Journal of Clinical Pathology 66;4:
335–42
A Non-linear Model
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 47
Thyroid‘s Secretory Capacity
Symbol Explanation Value
T Dilution factor for T4 (reciprocal of apparent volume of distribution) 0.1 l-1
T Clearance exponent for T4 1.1 * 10-6 sec-1 DT EC50 for TSH 2.75 mU/l K41 Dissociation constant T4-TBG 2 * 1010 l/mol
K42 Dissociation constant T4-TBPA 2 * 108 l/mol
Dietrich JW, Stachon A, Antic B, Klein HH, Hering S. The AQUA-FONTIS study:protocol of a multidisciplinary, cross-sectional and prospective longitudinalstudy for developing standardized diagnostics and classification of non-thyroidalillness syndrome. BMC Endocr Disord. 2008 Oct 13;8:13. doi:10.1186/1472-6823-8-13. PMID 18851740
GT =βΤ (∆Τ + [ΤΣΗ ])(1+ Κ41[ΤΒΓ ] + Κ42[ΤΒΠΑ])[ΦΤ4 ]
αΤ [ΤΣΗ ]
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 48
AQUA FONTIS G Trial
94 Patients
Inclusion criteria:
ICU treatment ≥ 24 hours
TSH < 0,5 mIU/l
Exclusion criteria:
Pregnancy
Manifest AIDS disease
Impossibility to distinguish between hyperthyroidism and NTIS in a
retrospective manner
Jeyabalan et al. unpublished
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 49
Patients‘ Characteristics
Sex 26 female, 68 male
Age 16 – 92 years, median 67 years
APACHE II 2 – 31, median 12
SAPS II 7 – 71, median 40
Prognosis 12 died 82 survived
CPR 15 resuscitated 79 no CPR
LOSIH 1 – 159, median 13
LOSICU 1 – 89, median 5
Hyperthyroidism 12 with hyperthyroidism 82 with NTIS
Jeyabalan et al. unpublished
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 50
Results
* p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 1e-4 Jeyabalan et al. unpublished
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 51
Results
Jeyabalan et al. unpublished
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 52
Results
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 53
Diagnostic Utility
‡: Optimal Parameter Jeyabalan et al. unpublished
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 54
Algorithm
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 55
GT 25,56GD 8,5TSHI 1,27sTSHI –2,11
1,41–8,67 pmol/s20–40 nmol/s
1,3–4,1–2–+2
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 56
GT 25,56GD 8,5TSHI 1,27sTSHI –2,11
1,41–8,67 pmol/s20–40 nmol/s
1,3–4,1–2–+2
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 57
GT 25,56GD 8,5TSHI 1,27sTSHI –2,11
1,41–8,67 pmol/s20–40 nmol/s
1,3–4,1–2–+2
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 58
The “TSH Reference Range War”
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 59
The “TSH Reference Range War”
Andersen S, Pedersen KM, Bruun NH, Laurberg P. Narrow individual variations inserum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab. 2002 Mar;87(3):1068-72. PMID 11889165.
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 60
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 61
MiMe-Log Model
Goe
de S
L, L
eow
MK
, Sm
it JW
, Kle
in H
H, D
ietr
ich
JW.
Hyp
otha
lam
us-p
ituita
ry-t
hyro
id fe
edba
ck c
ontr
ol: i
mpl
icat
ions
of
mat
hem
atic
al m
odel
ing
and
cons
eque
nces
for
thyr
otro
pin
(TS
H)
and
free
thyr
oxin
e (F
T4)
ref
eren
ce r
ange
s. B
ull M
ath
Bio
l. 20
14
Jun;
76(6
):12
70-8
7. d
oi: 1
0.10
07/s
1153
8-0
14-9
955-
5.
PM
ID 2
4789
568.
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 62
MiMe-Log Model
Goede SL, Leow MK, Smit JW, Dietrich JW. A novel minimal mathematical model of the hypothalamus-pituitary-thyroid axis validated for individualized clinical applications. Math Biosci. 2014 Mar;249:1-7. doi: 10.1016/j.mbs.2014.01.001. PMID 24480737
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 63
MiMe-Log Model
#Pre-Surgery TSH (mIU/L)
Pre-Surgery FT4 (pmol/L)
Setpoint TSH Setpoint FT4 |Delta TSH| |Delta FT4|
1 0.23 14.2 1.22 14.7 0.99 0.4
2 1.15 10.3 0.91 11.2 0.24 0.7
3 0.04 10.3 1.09 6.3 1.05 3.1
4 1.42 10.3 4.94 9.3 3.52 0.8
5 1.16 10.3 1.64 12.6 0.48 1.8
6 1.29 11.6 1.63 10.9 0.34 0.5
Mean 1.10 1.22
Cases from NOMOTHETICOS trial (clinicaltrials.gov NCT01145040)
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 64
Reconstruction of Set Point
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 65
SYSTEMS ENDOCRINOLOGYSYSTEMS BIOLOGY @ SYSTEMS MEDICINE
J. W. DIETRICH20141126
Doctoral Students:Antje AckermannAbira JeyabalanYarlini KanthasamyThabothini TharmalingamAline UrbanSeverina VasilevaGabi LandgrafeJan Giebelstein
Technical Assistance:Christine Fischer-Lahdo
Cooperation Partners:Elisabeth Conrad-OpelSteffen HeringRoland KöditzJohn E. M. MidgleyRudolf HörmannR. LarischRudolf KöhrleIna LehmphulJan W. SmitSam GoedeMelvin K. Leow
Advisors and General Support:C. Renate PickardtUlla Mitzdorf †Bernhard O. BöhmHarald KleinMatthew Marler