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2003 New Directions Short Course
Cellular Physiology
June 16-27, 2003


All lectures will be held in 409 Lind Hall

From June 16-27, 2003 the IMA will host a two-week intensive short course designed to efficiently provide mathematicians the basic knowledge prerequisite to undertaking interdisciplinary research in the burgeoning field of mathematical biology at the cellular level.  The course in Cellular Physiology will be taught by James Keener, Professor of Mathematics and Adjunct Professor of Bioengineering at University of Utah and author of the award-winning text Mathematical Physiology and Alexander Mogilner, Professor and Chancellor's Fellow at the Department of Mathematics and Center for Genetics and Development at University of California at Davis.  Participants will receive full travel and lodging support during the workshop.

Participants will gain an understanding the key mathematical issues in the topic, some familiarity with the relevant literature, ideas about problems to whose resolution they can contribute, and the basic knowledge necessary to initiate meaningful interdisciplinary collaborations in the field.

Short Course: Cellular Physiology, June 16-27, 2003

Cellular physiology is an area in which mathematical techniques are greatly needed and research opportunities abound.  It is a vital part of the rapidly growing field of mathematical biology.

The goal of the course will be to prepare qualified participants to start collaborative interdisplinary research in the area.  The course has two main components.  One component deals with the science of mathematical biology, and covers

  • The modern state of mathematical biology with emphasis on application in molecular and cell biology and physiology;

  • The mathematical tools ubiquitous in modern mathematical biology;

  • Prominent success and failure cases in mathematical biology.
The second component is designed to provide the participants with the 'soft skills' needed to in a multidisciplinary research collaboration, and involves
  • Presentations on the style mathematical modeling appropriate and necessary in modern computational biology;

  • Problems solving session in which the participants are engaged in modeling of typical cell biological phenomena.
The overall goal of the course will be to familiarize the participants with specific mindset and style of the field of the modern mathematical biology, and to enable them to start working in the field on their own. The overall structure of the course will be three lectures per day (two in the morning, one after lunch) followed by a working problem solving/discussion.

An important feature of this course will be the problem solving sessions.  For these the instructors will choose several biological problems from "hot" fields (e.g., signal transduction, biochemical regulation), collectively identify corresponding modeling problems, "brain-storm" the model, formulate model equations and delineate their solutions, analyze the solutions together. An attempt will be made so that these sessions represent a realistic demonstration of the interaction between theoreticians and experimentalists.

Additional lectures, meant to provide the participants with valuable insights into the field, are more informational in nature,
and will be more in the format of discussion sessions. An invaluable part of the program will be informal discussions with the participants, in which the instructors will help them to bridge their own current mathematical research with biological applications and suggest ways to find collaborators and new topics.

Textbook resources for this material:

  1. J. Keener and J. Sneyd, Mathematical Physiology, Springer 1998,
  2. C. Fall, E. S. Marland, J. M. Wagner, and J. J. Tyson, Computational Cell Biology, Springer, 2002.
Local arrangements

The participants of the short course and the instructors will be housed at one of the University of Minnesota's dormitories.  Meals will be served at the the dormitory dining facility.  Each participant will be provided with shared office space including an individual computer workstation. Lectures and problem-solving sessions will use the IMA's classroom, multimedia, and computer facilities.  There are expected to be visits to relevant laboratories on the University of Minnesota campus.    

Selection Process:

The criteria used in selecting the 25 successful applicants include:

  • Excellence of the applicant's scientific backgrounds and accomplishments;
  • The level of commitment of the applicant to redirection of his/her research profile;
  • The soundness of the research plan for the year in view of the candidate's background and goals;
  • The potential broadening of and impact to the applicant's research program;
  • The potential of the visitor to contribute to the advance of science in new areas in the years following the visit;
  • The visitor's plans for follow-up activities both in research and education; and
  • The potential of the applicant to contribute to the IMA program.

IMA New Directions Short Course - Schedule
All lectures will be held in 409 Lind Hall
Short Course Materials/Slides
Typical Daily Schedule
8:30-10 am General Lecture
10-10:30 am Break
10:30 am-12 noon General Lecture
12 noon-1:00 pm Lunch
1:00-2:00 pm Topical Lecture
2:00-2:30 pm Break
2:30-4:30 pm Problem/Brainstorming Session
On Monday, June 16, at 4:00 pm  there will be a reception in 400 Lind Hall.
June 25 at 6:30 Dinner at Gardens of Salonica
19 Fifth Street NE, Minneapolis, Tel (612) 378-0611.

Suggested Topics
Day Lecture 1 Lecture 2 Topical Lecture Problem Ideas
Short Course Slides/Materials click here
6/16 Introductions Enzyme kinetics
Slides:   html
Bacterial chemotaxis
Slides: pdf
James P. Keener
biochemical switches lac operon
quorum sensing in V.fisheri
6/17 Cellular homeostasis
Slides:   html
molecular motors I
Slides: pdf
Kathryn Tosney
growth cone motility
homeostasis of T. californicus
6/18 Excitability
HH Theory
Slides: html    pdf
ps    ppt
molecular motors II
Slides: pdf
Alexander Mogilner
model of cell crawling: nematode sperm cell

 

survival mechanism of h. pylori
6/19 Calcium
EC Coupling
Slides:
html    pdf
ps    ppt

Slides for Calcium Model:  html

muscle contraction
Slides: pdf
David Odde
kinetochore microtubule dynamics

Slides:   pdf

 
6/20 cell cycle
Slides:   html
physics of biological gels
Slides: pdf
Lihsia Chen
cell adhesion
(no problem session today)
6/23 Intercellular Communication
Slides:   html 
cell migration
Slides: pdf
Robert Sheaff
cell cycle control
Slides:   html    pdf ps    ppt
regul.&differ. of urothelial cells
6/24 Axons and Waves neutrofil chemotaxis
Slides: pdf
Clifton Ragsdale
neural connection
Paper: AgarwalaS'01.pdf

Background Info: WolpertTIGS'96.pdf

calcium waves in C. elegans
6/25 Gels, biofilms and quorum sensing
Slides:   html
pdf    ps    ppt
large gen & biochem networks
Slides: pdf
Ron Siegel
gel drug delivery
Slides:   html   pdf    ps    ppt
action poten. propag. in frog myocytes
6/26 Spatial patterns and signals
Lecture Link |Local Copy
modeling
morphogenesis

Slides: pdf
Bob Tranquillo
tissue growth
genetic basis of circadian rhythms
6/27 Report on Calcium Homeostasis
Slides:   html
morphogenesis in Drosophila Oscillatory Behavior in E. Coli During Lactose
Utilization
Slides:
  html
(no problem session today)

Titles

Short Course Slides/Materials click here
Additional references for the Calcium Homeostasis problem

  • Growth cone motility and guidance, Kathryn Tosney Molecular, Cellular and Developmental Biology Department, University of Michigan, Ann Arbor, MI 48109

    Abstract: The "growth cone" is the pathfinding organ of the neuron. It is the motile tip of the neuronal axon. It extends cellular processes, filopodia (dynamic cellular extensions containing actin bundles), that are essential for the axon to navigate to its proper destination. Little is known about the dynamics or signaling mechanisms, although a first step in initiating signal cascades is often filopodial adhesion. In contrast to the general assumption that all cell-substrate adhesions play equivalent roles, our studies establish that adhesions made by individual filopodia can mediate different and distinctive functions. The roles of filopodia and their adhesions in motility and guidance will be reviewed in this talk.

    Adhesions at three sites in individual filopodia were found to have dissimilar functions. Tip adhesions suffice to signal. Adhesions made by single filopodial tips can initiate signal cascades that systematically alter cytoskeletal dynamics. Alterations are discrete, robust, and suffice to mediate specific growth cone turning behaviors. Basal adhesions form at nascent filopodial bases before filopodia emerge, remain at bases throughout filopodial lifetimes, and function in filopodial emergence and dynamics. They specifically associate with "focal rings," newly described organelles that link actin bundles to the basal adhesion and thereby mediate substrate anchorage. Focal rings also develop in Schwann cells and other cell types. Shaft adhesions lie along filopodial shafts, lack focal rings, and control the extent of lamellar ("veil") advance. Shaft adhesions inhibit veil advance. Veils are unaffected by basal adhesions, but readily advance along filopodia until they encounter shaft adhesions, where they stop advancing. Most intriguing, navigational cues can guide by targeting shaft adhesions. Filopodial tip adhesion to an inhibitory cue induces shaft adhesions and abolishes veil advance, whereas tip adhesion to a permissive cue prohibits shaft adhesions and promotes veil advance. Shaft adhesions can thus regulate both motility and navigation. The discovery of functionally distinctive adhesions compels a reevaluation of signaling mechanisms that were previously inferred under the assumption that adhesions are mono-functional. The discovery also shows that guidance responses are much more discrete and invariant than previously supposed, and are thus good candidates for mathematical modeling. Support: NSF-0212326.

    Recent, relevant papers:

    Steketee M., K.W. Tosney. (1999). Contact with isolated sclerotome cells steers sensory growth cones by altering distinct elements of extension. J. Neurosci. 19: 3495-3506

    Polinsky, M., K. Balazovich and K.W. Tosney (2000). Identification of an invariant response: Contact with Schwann cells induces veil extension in growth cones. J. Neurosci. 20: 1044-1055.

    Steketee, M., K.J. Balazovich and K.W. Tosney (2001). Filopodial initiation and a novel filament-organizing center, the focal ring. Mol. Biol. Cell. 12: 2378-2395.

    Steketee and Tosney (2002) "Three functionally distinct adhesions in filopodia: Shaft adhesions control lamellar extension." J. Neurosci. 22:8071-8083.

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  • MODELING THE ROLE OF TENSION IN YEAST KINETOCHORE MICROTUBULE DYNAMICS, David Odde, University of Minnesota, Biomedical Engineering, Minneapolis, MN

    Abstract: To properly segregate replicated chromosomes during mitosis requires the formation of a mitotic spindle, which consists of microtubules that emanate from the spindle poles and connect to chromosome-associated kinetochores. Kinetochores track along microtubule plus ends as the microtubules self-assemble and disassemble via dynamic instability. Due to the stochastic nature of microtubule dynamic instability, the sister kinetochores can transiently move away from each other, each kinetochore tracking along a disassembling microtubule. In this case, tension will develop between the kinetochores in the chromatin that links them together. Prior work suggested that tension influences the switching behavior associated with dynamic instability. We found that a Monte Carlo simulation model for microtubule dynamic instability that includes tension-mediated microtubule switching was consistent with experimental observations of both wild-type and replication-deficient GFP-tagged yeast kinetochores during metaphase. This model also requires that a stable spatial gradient of microtubule catastrophe rate exists, with a higher probability of catastrophe (stochastic switching from self-assembly to disassembly) occurring at the spindle equator than at the poles. Together, these processes can account for the spatial organization of yeast kinetochore microtubules and the results suggest that tension in the kinetochore-DNA complex promotes the stabilization of microtubules and protects them from disassembly.

    Relevant reference: Brian L. Sprague , Chad G. Pearson , Paul S. Maddox , Kerry S. Bloom , E. D. Salmon and David. J. Odde , Mechanisms of Microtubule-Based Kinetochore Positioning in the Yeast Metaphase Spindle Biophysical Journal 84:3529-3546 (2003)

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  • L1 CAM is required for proper neuronal placement embryogenesis, Lihsia Chen, Department of Genetics, Cell Biology and Development, University of Minnesota

    Abstract: LAD-1, the sole homologue of the L1 family of neuronal cell adhesion molecules (L1CAMs), is required for nervous system development as well as embryogenesis. Indeed, we show that mutations in lad-1 result in Unc coilers that are Egl and constipated, as well as 40% embryonic lethality. Further analysis reveals misplacement of neuronal cell bodies in the mutants.

    LAD-1 contains an ankyrin binding motif, FIGQY, which allows LAD-1 to bind UNC-44 ankyrin and be linked to the spectrin-actin cytoskeleton. We show that LAD-1 is phosphorylated at the tyrosine residue of the FIGQY motif; this phosphorylation event is dependent on the egl-15 FGFR-activated Ras pathway. Phosphorylated LAD-1 is localized to axon-muscle and epithelial adherens junctions that are free of non-phosphorylated LAD-1, suggesting distinct functions for phosphorylated LAD-1. Indeed, phosphorylated L1CAMs have been reported to bind doublecortin, a microtubule-associated protein. This suggests that phosphorylation is a mechanism for LAD-1 to switch from actin to microtubule cytoskeletal linkage.

    Doublecortin is thought to play a role in neuronal migration. Thus, the biochemical interaction between doublecortin and L1CAMs is particularly intriguing in light of the neuronal misplacement defects observed in the lad-1 mutant. C. elegans contains a single doublecortin homologue, zyg-8, which was previously shown to play a role in mitotic spindle positioning. We show that the zyg-8 postembryonic mutants exhibit a similar phenotype to those of the lad-1 mutant: Unc and constipated coilers as well as high levels of embryonic lethality. This result suggests that the biochemical interaction between phosphorylated L1CAMs and doublecortin is functionally significant. We are in the process of genetically assaying if zyg-8 and lad-1 functionally interact.

    Recent relevant publication:

    Chen, L., Ong, B., and Bennett, V. 2001. LAD-1, the C. elegans L1CAM family homologue, has essential cell adhesion roles in the early embryo, participates in cell migration, and is a substrate for phosphotyrosine-based signaling. Journal of Cell Biology 154: 841-855.

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  • The role of Cyclin E-Cdk2 in the cell cycle, Robert Sheaff, University of Minnesota Cancer Center

    Recent relevant publications

    Genes and Development 11 (1997) 1464-1478

    Biophysical Chemistry 79 (1999) 95-105

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  • Patterning, Growth and Morphogenetic Fields in Brain Development, Clifton Ragsdale, Department of Neurobiology, Pharmacology and Physiology, The University of Chicago

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  • Models of an autonomous Rhythmic Hormone Delivery System, Ron Siegel, Department of Pharmaceutics, University of Minnesota

    Certain disorders in sexual development and reproductive function are traced to disorders in the rhythmic, pulsatile secretion of gonadotropin releasing hormone (GnRH) from the hypothalamus. These disorders may require long-term hormone replacement therapy, and rhythmic delivery of GnRH is essential. Since GnRH is exceptionally potent, implantable hormone delivery systems may be considered. We are developing such a system, in which autonomous modulation of permeability of a hydrogel membrane to GnRH is driven by endogenous glucose, via a chemomechanical limit cycle established by feedback between the membrane and an enzyme. Several mathematical models of this system have been developed, with different levels of complexity. We will present results of a lumped, ODE-based model, for which the bifurcation structure has been worked out, and will also progress towards a more detailed, distributed (PDE-based) model.

    Recent relevant publications:

    J. Controlled Release 81 (2002) 1-6

    J. Controlled Release 29 (2002) 1293-297

    J. Chemical Phys. 110 (1999) 2267-2279

    Chaos 9, 267-275 (1999)

    Chaos 10, 682-690 (2000)

    J. Phys. Chem.A 106, 8835-8838 (2002)

    J. Pharm. Sciences 91 2026-2039 (2002)

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  • Tissue Growth in Cell-Contracted Biopolymer Scaffolds, Robert T. Tranquillo, Departments of Biomedical Engineering, and Chemical Engineering & Materials Science, University of Minnesota

    We have attempted to develop a tissue-engineered artery and heart valve based on the approach of entrapping tissue cells within a forming collagen gel. The ability to harness the cell traction-induced contraction of the network of collagen fibrils to obtain the desired alignment of fibrils and cells will be described and explained. Recent efforts to drive "compositional remodeling" following the "structural remodeling" obtained via mechanically-constrained contraction, using fibrin as an alternative biopolymer to collagen for cell entrapment, with the goal of attaining the requisite mechanical properties, will be presented. Unlike the early "structural remodeling", the subsequent "compositional remodeling" and associated tissue growth that occurs in fibrin presents major modeling challenges.

    Recent relevant publications:

    A novel implantable collagen gel assay for fibroblast traction and proliferation during wound healing.
    Enever PA, Shreiber DI, Tranquillo RT.
    J Surg Res. 2002 Jun 15;105(2):160-72.

    Short Course Slides/Materials click here
    Group Photos

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    LIST OF NEW DIRECTIONS SHORT COURSE PARTICIPANTS
    As of 6/11/2003
    Name Department Affiliation
    Vasilios Alexiades Mathematics Department University of Tennessee
    Steven Buechler Mathematics University of Notre Dame
    Paul E. Castillo Center for Applied Scientific Computing Lawrence Livermore National Laboratory
    John W. Dold Mathematics UMIST
    Christopher E. Elmer Mathematical Sciences New Jersey Institute Of Technology
    Donald French Mathematical Sciences University of Cincinnati
    Yixin Guo Mathematics University of Pittsburgh
    Alex Himonas Mathematics University of Notre Dame
    Wilhelm Huisinga Institute of Mathematics and Computer Science Free Institute (FU) Berlin
    James P. Keener Mathematics University of Utah
    Brynja Kohler Mathematics University of Utah
    Aihua Li Mathematics and Computer Science Loyola University New Orleans
    Frank Lynch Mathematics University of Utah
    Brian Martensen Mathematics University of Texas at Austin
    Alex Mogilner Mathematics University of California, Davis
    Peter K. Moore Mathematics Southern Methodist University
    Bjorn Fredrik Nielsen   Simula Research Laboratory
    Trygve Kastberg Nilssen   Simula Research Laboratory
    Seth Oppenheimer Mathematics and Statistics Mississippi State University
    J. Maurice Rojas Mathematics Department Texas A&M University
    Bjorn Sandstede Mathematics Ohio State University
    Milena Stanislavova Mathematics University of Kansas
    Edwin Tecarro Biomathematics UTMD Anderson Cancer Center
    Anthony Tongen Mathematical/Computer Information Systems Trinity International University
    Janos Turi Mathematics University of Texas-Dallas
    Li Wu Mathematics University of Rhode Island
    Yuncheng You Mathematics University of South Florida
    Ming Zhang Biomathematics University of Texas-Houston

    Group Photos

    Short Course Materials/Slides

    Registered Participants Information

    IMA New Directions Program

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