Dynamic control in selective leukocyte recruitment.

Format:

Book

Thesis/Dissertation

Author/Creator:

Beste, Michael Thomas.

Contributor:

Hammer, Daniel A., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Immunology.

Chemical engineering.

0542.

0982.

Penn dissertations--Chemical and biomolecular engineering.

Chemical and biomolecular engineering--Penn dissertations.

Local Subjects:

Penn dissertations--Chemical and biomolecular engineering.

Chemical and biomolecular engineering--Penn dissertations.

0542.

0982.

Physical Description:

223 pages

Contained In:

Dissertation Abstracts International 70-06B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

How do blood-borne immune cells navigate the circulation and selectively position themselves among distinct tissue compartments? This question has been the focus of intense study since leukocyte rolling and migration were first described by pathologists in the nineteenth century. Leukocyte trafficking is now understood to be of central importance in the maintenance of systemic immunity, and many of the underlying mechanisms that regulate leukocyte adhesion and recruitment have begun to be elucidated. Yet despite many conceptual advances, the scope of molecular interactions implicated in the trafficking program has proven to be enormously complex and not amenable to simple, reductionist descriptions.

In this thesis, we develop a family of mathematical models describing leukocyte recruitment which provide a natural framework for dissecting increasing levels of biological complexity. This strategy entails three related aims: (1) to identify intrinsic molecular properties that govern adhesion equilibria between leukocytes and their substrates; (2) to define how mechanochemical variations among adhesion receptors affect leukocyte kinematics; and (3) to describe how intracellular signaling events dynamically regulate the transition between equilibrium adhesion states. We first developed a minimal mathematical model and identified physical regimes in which receptor-mediated adhesion is either monostable or bistable. Incorporating more detailed descriptions of receptor mechanochemistry then allowed us to define precise molecular requirements that give rise to shear-enhanced leukocyte rolling. Finally, we constructed a spatio-temporal model of the signaling networks known to activate leukocyte adhesion. By integrating simulations of adhesion and signaling, we recapitulated characteristic dynamics of leukocyte recruitment and predicted a role for combinatorial ligand recognition in generating tissue- and cell-specific homing patterns among heterogeneous populations of T lymphocytes.

Notes:

Thesis (Ph.D. in Chemical and Biomolecular Engineering) -- University of Pennsylvania, 2009.

Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3652.

Adviser: Daniel A. Hammer.

Local Notes:

School code: 0175.

ISBN:

9781109224467

Access Restriction:

Restricted for use by site license.