Funding opportunities

Phenotyping Human Astrocytes in Health and Disease

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06041
Principle Investigator: 
Institution: 
Funds requested: 
$1 385 517
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
An emerging theme from recent research is that autism and schizophrenia are diseases of synapses, the interconnections through which electrical signals are relayed from one neuron to the next neuron in a neural circuit. Up to now, most research has focused on new therapeutics that would target neurons and enhance the number of function of synapses in these diseases. However, recent research has shown that the supporting cells of the brain called astrocytes may represent exciting new therapeutic targets. Long thought to be primarily passive support cells, recent studies have established that astrocytes secrete signals that powerfully stimulate the formation and function of synapses throughout the brain. In this proposal, we will take advantage of induced pluripotent stem cell (iPSC) technology to study the ability of astrocytes derived from iPSCs from patients who have autism and schizophrenia. We will also generate new methods to more quickly generate human astrocytes from iPSCs. These studies have the potential to shed new light on the basis of autism and schizophrenia in humans, and to generate new methods and drug testing platforms for human astrocyte generation from iPSCs.
Statement of Benefit to California: 
Neurodevelopmental disorders including autism and schizophrenia affect many Californians. An emerging theme from recent research is that autism and schizophrenia are diseases of synapses, the interconnections through which electrical signals are relayed from one neuron to the next neuron in a neural circuit. Up to now, most research has focused on new therapeutics that would target neurons and enhance the number of function of synapses in these diseases. However, recent research has shown that the supporting cells of the brain called astrocytes may represent exciting new therapeutic targets. Long thought to be primarily passive support cells, recent studies have established that astrocytes secrete signals that powerfully stimulate the formation and function of synapses throughout the brain. In this proposal, we will take advantage of induced pluripotent stem cell (iPSC) technology to study the ability of astrocytes derived from iPSCs from patients who have autism and schizophrenia. We will also generate new methods to more quickly generate human astrocytes from iPSCs. These studies have the potential to shed new light on the basis of autism and schizophrenia in humans, to generate new methods and drug testing platforms for human astrocyte generation from iPSCs, which ultimately are critical to help lead to new therapeutics for patients suffering from neurodevelopmental disorders.
Review Summary: 
This proposal focuses on the role of astrocytes as a therapeutic target in neurodevelopmental disorders involving synaptic dysfunction, such as autism and schizophrenia. The applicants plan to utilize human induced pluripotent stem cell (hiPSC) technology to establish an in vitro astrocyte culture system that can be used for both drug testing and pathophysiology studies. This study aims to improve methods of human astrocyte generation from hiPSCs, develop the in vitro astrocyte culture system, and investigate the contribution of astrocyte defects to the pathophysiology of a synaptic disorder by using patient-derived hiPSCs. Significance and Innovation - The proposed study of astrocytes in synaptic disorders is important, understudied, and could advance the field. - The novelty of the study lies in the first attempt made to characterize astrocytes in the targeted spectrum of disorders. - The applicant proposes to utilize an innovative approach to enrich for astrocytes, but otherwise uses routine assays. Feasibility and Experimental Design - Though the applicant is experienced in the field, the data provided in the application did not sufficiently support the experimental design. For example, astrocyte generation is slow and the preliminary data supporting the ability of the applicant to generate astrocytes more quickly is weak. It will be a technical challenge to culture sufficient numbers of cells for a sufficient amount of time to complete the proposed experiments. - All the appropriate tools and resources are in place. However, based on the application, the applicant does not appear to appreciate some of the issues that may occur with astrocyte generation from hiPSC and with disease modeling using the proposed cell culture system. - Reviewers expressed concern that the applicant has not selected the most appropriate patient cohort. One of the selected cohorts exhibits a defect in a synaptic protein. While there could be other genes involved this should have been considered since this application is focused on astrocyte contributions to disease. - Overall, the aims and timelines are feasible. However, reviewers expressed concern that the applicants indicate a 5-year timeline whereas this is a 3-year award. This discrepancy is reflective of a lack of grantsmanship in the proposal and will need to be rectified prior to funding. - The proposal is rational and logical and builds on work done by this team. Principal Investigator (PI) and Research Team - The PI is an outstanding investigator who has made outstanding contributions to the field of study. However, the PI’s lack of sufficient commitment to this research is one of the major concerns and risks to this project. - The postdoctoral fellow proposed to lead the project does not have sufficient experience to compensate for the PI’s low level of commitment. - The co-investigator is a strong collaborator who adds to the project. Responsiveness to the RFA - This project is responsive to the RFA, and no relevant concerns were highlighted by reviewers under this review criterion.
Programmatic review: 
  • PROGRAMMATIC DISCUSSION
  • A motion was made to move this application into Tier 1, Recommended for Funding. This application was raised for discussion when reviewers expressed an interest in considering applications focused on autism. Though it was noted that this application is focused on astrocytes rather than autism, the panel agreed that it addresses an important and understudied question and represents a novel topic that is worth funding despite the risks of the application (the low overall commitment of the PI and the weak preliminary data). The review panel urged the applicant to carefully consider the patient cohort before proceeding with this important study and indicated this is a key issue for discussion with the applicant during the pre-funding period should the board approve this application for funding. The motion carried.
Conflicts: 
  • Ali Brivanlou

© 2013 California Institute for Regenerative Medicine