Download R24Summary Statement - University of Illinois Archives

RESUME: This is an application for a large-scale collaborative project to examine the properties
of neuronal dendrites. There are advantages to looking at dendrites rather than at single cells, and
the investigators are well suited to the task. Too little emphasis seems to have been placed on the
physiology of dendrites, and there was some discussion that the proposed industrial collaborator
might not be the most appropriate. The administrative aspects of the proposed collaborative
effort appear to have been well thought out. Despite the relatively minor concerns raised, this is a
timely area for further investigation, and the potential for a synergistic effort that will result in
important new information is substantial.
DESCRIPTION: This project focuses on the dendrites of neurons and includes a group of 22
investigators in the field of dendrite biology. The principal investigators are James Eberwine,
Ph.D., Department of Pharmacology and Psychiatry, University of Pennsylvania, and William T.
Greenough, Ph.D., Department of Psychology, Psychiatry and Cell and Structural Biology,
Beckman Institute, University of Illinois.
The major scientific initiatives, all focused on dendrites, are: mechanisms of dendrite protein
synthesis; trafficking of messenger RNA (mRNA), protein synthesis components and proteins;
mechanisms of receptor signaling and interactions among signaling pathways; and generation
and flow-of-information-bearing electrical signals within and between dendritic compartments.
One initiative that will tie all of the investigators together s called "discerning the elements of
plastic neuronal change."
CRITIQUE: There is no question that greater conceptual insight into dendrites is very desirable.
There is also no question that the group of investigators that have been assembled have the
requisite expertise. Although the phase I proposal itself does not present particularly novel ideas,
there are compelling scientific reasons to encourage a "dendrite biology consortium" at this time.
Dendrites are the major sites of input to individual neurons. The background material presented
lays out nicely the intellectual history of dendrite biology. We now recognize that dendrite
chemistry and geometry are subject to modification through experience, providing one cell
biological locus for understanding potentiation, learning, and memory.
The proposal claims, with some justice, that the geometry of neurons gives students of this
biology an advantage over those who study information processing in other kinds of cells. The
geometrical specializations of neurons place much of the information input in one region of the
cell, albeit a big one. This provides a conceptual and a practical approach to working out
complex information processing pathways. Since it is now well demonstrated that dendrites not
only contain enzymes that modify existing proteins but also the machinery for protein synthesis,
several aspects of the general mechanisms for cellular information processing will almost
certainly emerge from the kinds of studies proposed here. Other studies, not emphasized in the
proposal, show that neuronal signals induce changes in levels of transcription, which in turn have
impact on the proteins that can be synthesized at any one time. This aspect of both neuronal and
general cellular information processing may not be so well assessed by the strategy that the
proposal describes. It is, however, possible in their system to look directly at the ways in which
mRNA is moved within cells and how this process might be regulated. This aspect of "central
dogma" information processing is likely to be of significance in neurons. While it may be less
important in other cells, it is nonetheless a process that is well worth trying to understand.
The science that will be undertaken with this collaborative effort is of great importance. The
problem described is sufficiently complex that the major collaborative funding mechanism seems
an appropriate way to enhance the science being done; the idea of tackling such a hard project in
this way makes good sense. One example in support of this view is the interaction that is now
being discovered between signaling pathways that were previously regarded as independent, or
perhaps parallel. More recent work has revealed the extent to which such "pathways" talk to one
another at almost every step along the way, making them information processing networks rather
than pathways. Dendrites contain an enormous number of receptors that initiate a multitude of
signaling pathways, and the mindset of neuroscientists has, in general, been towards
understanding the ways in which these pathways might interact to help the cell to decide whether
or not to fire and how easily to fire in the future. This group is, therefore, poised to analyze
cross-talk between pathways from the very start, an important aspect of coming to grips with the
complexity of biological signaling and a nice justification for the collaborative efforts that are
proposed.
One concern is the paucity of initiatives that involve the "fast-signaling machinery" of the
dendrite. Given the very exciting progress in this general area, the relative absence of
electrophysiology in the proposed consortium is a potential weakness. The emphasis on slower
biochemical processes such as protein synthesis and mRNA trafficking undoubtedly reflects the
PIs' main expertise.
The PIs of this project are both leaders in their field, and the participating investigators are
numerous, widely situated. They present CVs that support the contention they are all wellestablished investigators with good track records for scientific productivity on their own and
collaborative activity more generally. While the density of truly distinguished scientists is not as
high as one might like, each of the investigators seems well qualified to carry out the projects
they will undertake within this collaborative structure, and the whole fabric seems sound. In
addition, the group has already begun to develop important collaborative tools that take
significant advantage of internet communication and the excellent computer facilities at Illinois.
The designer of the biology workbench program is one of their collaborators, and he has
specifically designed an interactive computer tool called "neuro-informatics universal workbench
for analysis and environment" (NIUWAE), which is an integral part of the project proposed. This
and other specific plans for collaborative interaction give credibility to this interactive proposal.
However, there was some discussion whether the commercial collaborator proposed was
appropriate. The administrative plan seems reasonable, and the PI has clearly thought through
many of the key issues involved, including intellectual property and the details of project
management. The only universal criticism of the proposal by all reviewers was that the choice of
font was small enough to make reviewing it quite difficult.
BUDGET: The budget is recommended as requested.
HRS