The institutions
participating in this proposal are Pitt, PSC, CMU, and Duquesne
University. A major goal of our joint
activities, including but not limited to this proposal, is to bridge the
different talents and cultures represented by experimental and computational
scientists working on biological problems.
In December 1999, in an effort to promote interaction between these
groups, we held a workshop of > 50 participants from the four institutions.
The experimental researchers understood each other and the computational types
communicated well, but there was less effective interaction across the
groups. There was, however, broad
recognition that the two groups needed each other and several initiatives arose
from this meeting; they were aimed at identifying both research problems that
spanned experiment and computation, and expertise required for their
solution. Several collaborations resulted
from that, including this proposal. However, if awarded, the pre‑NPEBC would be
embodied within a Pittsburgh Center for Biomedical Computing (PCBC) that would propel the community far beyond
the informal associations engendered thus far.
The specific opportunities
highlighted in this proposal have arisen from new collaborations between and
within computational and experimental research groups in the Pittsburgh area.
The computational aims focus on novel, integrative projects at multiple
temporal and spatial scales, with cutting-edge resources and technical
expertise available to carry growing projects into large-scale computation as
needed. The biomedical aims focus on important issues underlying cell
cycle control as it relates to DNA damage, apoptosis and signaling. Of course, this
encompasses a lot of territory:
molecular events, complexes and assemblies, local signaling between near
molecular neighbors (in solution and/or in membranes), distal signaling and
interactions between molecules in different cellular compartments, signaling at
the multicellular level. Another
hallmark of these events is the important role of stochastic processes, which in
vivo, are orchestrated into a symphonic whole in healthy circumstances,
while in disease that orchestration is often disrupted. The core focus of this proposal and the
opportunities it presents is to understand the integrating and organizing
aspects of these interactions.
A.1.2. Computational and
Biomedical Aims. The proposed Pre-NPEBC award will support infrastructure to develop new,
interdisciplinary collaborative projects focused on computational aims and biomedical
aims. The computational aims are:
1)
Development of new models and simulation environments
for multiscale investigation of cellular dynamics, focused on three areas of specialization:
(i) structural dynamics of macromolecular complexes and assemblies, (ii)
simulation of microphysiological processes with stochastic (Monte Carlo)
methods at hierarchical levels of spatial realism, and (iii) mathematical
modeling of the nonlinear dynamics of cellular networks
2)
Integration of the above three computational and
mathematical approaches, or bridging the gap between molecular and cellular
models of biological processes
3)
Development and implementation of computational and
mathematical tools for storage, visualization, and Internet accessibility of
the results and algorithms developed at multiple targeted scales.
The
planned biomedical aims are focused
on complex cell signaling and regulatory processes related to apoptosis and
cell cycle checkpoints, - areas in which detailed multiscale modeling is likely
to yield important insights (e.g. how can one signaling agent trigger either
pro-apoptotic or anti-apoptotic response, or what factors dictate the choice
between the activation of DNA repair machinery or the promotion of apoptosis,
in response to DNA damage?). Anticipated developmental projects (DP) include
studies on multiscale modeling of (i) the effects of nitric oxide (NO) on
apoptosis (DP1), (ii) cell signaling and regulation machinery in response to
DNA damage (DP2), and (iii) ligand
interactions with signaling molecules (DP3). These projects are linked by several
common molecules or common pathways, and they all pertain to the
regulation/dysregulation of the cell cycle at the G1/S and G2/M checkpoints.
They contain subprojects that explore the same problem, as viewed from
different perspectives: interacting molecules, cascades of interactions, or
networks of interactions containing complex feedback and control mechanisms.
The two groups of researchers, computational and biomedical, will coordinate
and integrate efforts towards the design of molecular control mechanisms
against dysregulation of cell cycle.