Funding opportunities

New Chemokine-Derived Therapeutics Targeting Stem Cell Migration

Funding Type: 
SEED Grant
Grant Number: 
Principle Investigator: 
Funds requested: 
$759 000
Funding Recommendations: 
Recommended if funds allow
Grant approved: 
Public Abstract: 
Statement of Benefit to California: 
Review Summary: 
SYNOPSIS: This proposal will design and synthesize novel analogs of the chemokine SDG-1-alpha in aim 1. The most potent and specific of these 'Synthetically and Modularly Modified Chemokines'(“SMM-chemokine analogs”) are expected to help mobilize and direct human neural stem cells (hNSCs) toward sites of CNS injury – in this case, a hypoxic ischemic (HI) cerebral injury. In specific aim 2, in vitro assays of the analogs will be performed including biochemical binding of ligands to their receptors and in vitro migration (e.g. Boyden chambers) followed by an in vivo screen of the most promising analogs in a model of hypoxic-ischemic cerebral injury in conjunction with hESC-derived NSC. INNOVATION AND SIGNIFICANCE: The idea of developing new potent and specific analogs of SDF-1 alpha to manipulate stem cell-host interactions is very innovative and potentially very important. STRENGTHS: This is a reasonably well-written proposal to study an important molecular “homing factor” in hNSC migration and integration in the brain. This work builds on previous studies from the Snyder group showing that the SDF-1-alpha/CXCR4 chemokine axis is very important for directed migration of other NSCs. The idea of manipulating “the molecular mechanism of chemokine-mediated stem cell homing and engagement” for better stem cell homing and integration is a major strength of this proposal. The PI is a productive and experienced investigator who has extensive experience with designing and using synthetic peptides to study the chemokine/receptor interactions and the actions of this chemokine pathway. There is an ongoing collaboration with Evan Snyder, an experienced stem cell biologist. WEAKNESSES: The proposal is based on the hypothesis that “…chemokines and their receptors…play important roles in mediating the directed migration of human neural stem cells (hNSCs) to, as well as engagement and interaction with, sites of CNS injury…” We already know this is true. The rationale for using hES cells is not terribly strong since many previous studies from this group have already used an adult neural stem cell line that might be more appropriate for the testing of new analogs and deriving hNSC from hESC represents an extra and unnecessary step. Most daunting about this proposal is that is seems that many parts have been already done or written for another grant. For example, in the Methods the PI states that organtopyic explants will be used (out of nowhere, since the migration assays in previous sections don’t seem to address this approach) from “adult C57BL6 mice …WERE SUBJECTED to permanent middle cerebral artery occlusion…” In another example, the PI states in the Abstract that, “…Here in this renewal application we propose to extend our research into a new area of stem cell biology and medicine involving chemokine receptors such as CXCR4 and its ligand SDF-1”… This would be great, but this RFA is new and not associated with any “renewals”. It is not clear why new ligand analogs of SDF-1alpha will also be tested for their decreasing or inhibiting monocyte/lymphocyte migration. This also seems like a leftover from ongoing or previous studies of the PI’s. This PI seems to have a great deal of committed percentage effort toward studying chemokines and heat shock protein-related factors for therapeutic development in cancer and infectious disease. It is not completely clear that the amount of work needed to perform the proposed studies can be fit into this exiting commitment. DISCUSSION: This represents a bit of a change of field and direction for the PI who has been focusing much of his previous attention on chemokines, XIAP family molecules, and other factors involved in cancer and infectious disease. Many people are interested in SDF-1alpha but very little is known about the role of SDF-1a/CXCR4 in NSC. There will be interest in analogs generated, thus potential for impact on field. The proposed work could have potential clinical significance because will direct hNSC to given area.

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