Bioengineering team chosen for National Academies Keck
Futures Initiative
New research at Rice University explores ways to model blood
vessel growth

BY SHAWN HUTCHINS
Special to Rice News

Rice University bioengineers Amina Qutub, Michael Diehl and Tomasz Tkaczyk are one of 13 groups of
collaborators chosen to conduct imaging research as part of the 2011 National
Academies Keck Futures Initiative (NAKFI).

This competitive seed grant enables interdisciplinary
research at the intersection of science, engineering and medicine, and enhances
education opportunities among the laboratories at Rice’s BioScience Research
Collaborative.

	AMINA QUTUB		MICHAEL DIEHL		TOMASZ TKACZYK

The project aims to analyze and model blood vessel growth
from subcellular to capillary network levels. It involves building multiscale
computer models of blood vessel growth from experimental wet-lab data using
Tkaczyk’s hyperspectral imaging techniques and a new class of erasable
molecular imaging probes, developed by Diehl, that monitor gene-expression
patterns in the vascular endothelial cells responsible for capillary
development. Qutub, the principal investigator on the project, will integrate
the complex biophysical data to test theories of capillary development, or
angiogenesis.

“Angiogenesis underlies wound healing, and the progression
of cancer, neurodegeneration and cardiovascular disease,” said Qutub, an
assistant professor in bioengineering. “But more rigorous studies in vascular
systems biology are needed to show how the molecular and cellular processes
work to keep tissues healthy. The models derived from this research will
greatly improve our understanding of how reduced levels of oxygen and nutrients
are linked to adaptive changes in cellular structure and function and,
consequently, how these changes drive capillary formation.”

Vascular endothelial cells, which line the interior of blood
vessels, respond to low levels of oxygen, or hypoxia, through a series of
molecular processes. The outcome produces a particular protein – hypoxia-inducible
factor-1 (HIF-1) – that becomes the basis for how future cells differentiate,
adapt and mediate blood-vessel sprouting behaviors. 

To effectively assess the complex endothelial cell-to-cell
interactions and measure hypoxic responses, the team will use new image-based
technologies developed by Diehl and Tkaczyk. 

Diehl, an assistant professor in bioengineering and in
chemistry, will adapt a new erasable molecular-imaging probe to determine the
expression profiles of several tens of key proteins that contribute to the
HIF-1 molecular pathway within individual cells. The DNA labeling procedure is
well-established and based on a proof-of-concept paper published in the Nov. 21, 2010,
journal Bioconjugate Chemistry.  

The imaging process involves sequentially attaching multiple
fluorescent probes that serve as colored beacons within the cell’s DNA to label
HIF-1 and monitoring its molecular pathways that guide angiogenesis.

“A unique feature of the probes is that the fluorescent
signals can be washed from a biological specimen through simple washing
procedures and without disrupting regular cell operations,” Diehl added. “This
is crucial given the vast number of molecular cell-pathway components that
participate in angiogenesis and the implicit relations between pathway status,
cell migratory status and tissue morphology.”

The imaging process, when combined with Tkaczyk’s
hyperspectral imaging instrument, will instantly reveal a biological specimens’
composition in an array of color that can simultaneously detect up to 10
different color dye targets. 

In a single snapshot and without the use of scanning techniques,
the hyperspectral imaging instrument captures a specimen and separates it into
zones using an image mapper, which is a series of long, thin, multi-angled
mirror facets. 

A high-resolution digital camera acquires this array of
information and correlates each active pixel with the encoded spatial and
spectral information. This volume of information is assembled like a jigsaw
puzzle by a laptop computer to instantaneously produce a 3-D data cube that can
be used at multiple imaging levels. 

“The nonscanning, snapshot nature of the system will allow
us to image a specimen repeatedly and for extended periods of time,” said
Tkaczyk, an assistant professor in both bioengineering and electrical and
computer engineering.

The high-resolution spatial molecular signaling data will be
coupled to observed cell behavior through probabilistic and graphical models.
Qutub said results of the multiscale modeling can be used to simulate
regeneration of capillaries as a function of hypoxia for applications in tissue
engineering, protein- and gene-based drug development, and synthetic
biology. 

“The integrated imaging-modeling approach will provide
unprecedented insight into how molecular changes drive cellular decision
making. In doing so, it makes what can seem like unfathomable complexity,
approachable,” Qutub said. 

Launched in 2003, NAKFI is a program of the National Academy
of Sciences, the National Academy of Engineering and the Institute of Medicine
with support from the W.M. Keck Foundation.

— Shawn Hutchins is a staff writer in the Department of
Bioengineering.