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Part I: Modeling of Hormone Feedback Networks

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BERE Symposium, Izmir, Turkey. Gonadotropins. 1) Are synthesized and released by hypothalamic neurons ... 2) Are transported by hypothalamic-hypophyseal portal ... – PowerPoint PPT presentation

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Title: Part I: Modeling of Hormone Feedback Networks


1
Part I Modeling of Hormone Feedback Networks
  • Understanding Endocrine Oscillations

Raina Robeva Sweet Briar College
June 14, 2009 BERE Symposium, Izmir, Turkey
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1947 DRS. J.D. Green G.W. Harris Hypothesized
that certain substances
  • 1) Are synthesized and released by hypothalamic
    neurons
  • 2) Are transported by hypothalamic-hypophyseal
    portal circulation to the anterior pituitary
    gland
  • 3) Influence the secretion of pituitary hormones

5
  • 1971-72 The Discovery of Gonadotropin
  • Releasing Hormone (GnRH)
  • A 10-amino acid peptide capable of stimulating
    the release of LH and FSH
  • Concentrated, purified and characterized from
    hypothalamic extracts from the
  • Pig (Matsuo and colleagues, BBRC 1971)
  • Sheep (Burgus and colleagues, PNAS 1972)

Schally Guillemin
6
  • Studies in the Rhesus Monkey from the
    Knobils Laboratory(1970-1980)
  • Lesioning of the medial basal hypothalamus
    abolishes gonadotropin secretion
  • Administration of GnRH in a continuous manner
    fails to restore gonadotropin secretion
  • Administration of GnRH in a pulsatile manner
    restores gonadotropin secretion
  • Administration of antibody to GnRH abolishes
    gonadotropin secretion

7
Pulsatile Secretion of Hormones
8
LH Pulsatility During the Human Menstrual Cycle
  • Pulse frequency (/24 hours)
  • Early follicular 14-24
  • Late follicular 17-29
  • Mid-luteal 4-16

9
The pattern of delivery is crucial to hormone
action
  • The action of many hormones is impaired if
    pulsatility is lost
  • Moreover, if a hormone is delivered continuously
    the effect could be negative
  • Therefore, understanding the forces driving
    hormone oscillations is particularly important in
    medicine and biology

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Challenges Two Competing Processes-- Secretion
and Ongoing Elimination
13
Challenges
  • Data points are very expensive to collect and
    process
  • The typical cost of a clinical laboratory assay
    is approximately 50 per sample
  • The Figure has 144 data points and each was
    assayed twice
  • The cost for the assays alone was approximately
    15,000
  • This does not include the clinical staff time,
    payments to the volunteer.

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Pulsatility Software
Michael Johnson, Ph.D Department of Internal
Medicine Division of Endocrinology and
Metabolism University of Virginia
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Method Output
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Question
  • With so many factors present in the hormone
    network, what would be a good approach to the
    problem?
  • How can a good mathematical model be developed?

good (relatively) simple useful
18
Wiring Diagrams
  • Rectangles used to denote system variables,
    e.g. GH, GHRH, SRIF
  • Lines indicate causality
  • Line labels () excitatory action
  • (-) inhibitory action
  • Triangles indicate delay
  • Ovals to indicate elimination

19
Feedback and Delayscan cause oscillations
20
Growth Hormone
  • The Growth Hormone (GH) is secreted from the
    pituitary gland under the control of substances
    released from the hypothalamus

21
Individual representative male rat GH profiles
Lanzi R. Tannenbaum, G. Time Course and
Mechanism of Growth Hormones Negative Feedback
Effect on its Own Spontaneous Release.
Endocrinology, Vol. 130, 2 (1992), 780-788.
22
Major factors controlling GH release
  • An universally accepted understanding is that
    pulsatile GH secretion is regulated by two major
    factors released from the hypothalamus
  • (GH stimulator) GH-releasing hormone (GHRH)
  • (GH inhibitor) somatostatin (SRIF)
  • Numerous other substances could impact the GH
    output. However, they are considered not to be
    responsible for the typical GH pulsatility

23
Elements of the GH network
  • GH, GHRH, SRIF, and the interconnections between
    them form the core GH network
  • Question Could this simplified network alone
    explain the typical rat GH rhythm?

24
Consensus GH Feedback Network
()

(
-
)

SRIF

GHRH

()

(

-

)

GH

D



25
Rate of change of hormone concentration
  • Elimination
  • Source controlled by other hormones

Secretion
Elimination
26
Physiological Meaning of the Parameters
Elimination
Secretion
27
Equivalent Formulation as a Convolution Integral
28
Steps of the Proof
1. Show that   2. Show that   3. Show that
  4. Finally, use that
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Modeling the Control of Secretion
  • Hill functions

n5 and T50
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Hormone A depends on Hormone B
B
A
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Hormone A depends on Hormone B
B stimulates the secretion of A
()
B
A
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Hormone A depends on Hormone B
B inhibits the secretion of A
(-)
B
A
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Hormone A depends on Hormone B
B inhibits the secretion of A with a delay of D
hours
(-)
B
A
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Example
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When hormones B and C affect the secretion of A
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The control function as a combination of Hill
functions
  • If B and C both stimulate A
  • Simultaneously
  • Independently

37
Consensus GH Feedback Network
()

(
-
)

SRIF

GHRH

Model output
()

(

-

)

GH

D


38
Individual representative male rat GH profiles
Lanzi R. Tannenbaum, G. Time Course and
Mechanism of Growth Hormones Negative Feedback
Effect on its Own Spontaneous Release.
Endocrinology, Vol. 130, 2 (1992), 780-788.
39
Presumed GH Feedback Network
Model output
40
How can a feedback model help?
  • It provides a possible physiological explanation
    of the behavior of complex endocrine systems.
  • Could be used for testing various hypotheses. It
    could quickly provide answers to non-trivial
    questions of the type what if, or it could
    simulate the eventual effect of the simultaneous
    actions of several factors.
  • It could be very helpful in the process of
    designing of new experiments, some of which could
    be very sophisticated and difficult to perform in
    the lab.
  • The interpretation of the experimental results
    can be significantly simplified.

41
  • William Evans, MD, Ph.D.
  • Leon Farhy, Ph.D
  • Department of Internal Medicine
  • Division of Endocrinology and Metabolism
  • University of Virginia

42
Discussion
  • Control functions accounting for the effect of
    multiple hormones
  • Delay
  • Why Hill functions?
  • Sensitivity Analysis
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