NIH Blueprint for Neuroscience Research: Tools and Technologies to Explore Nervous System Biomolecular Condensates (R21 Clinical Trial Not Allowed)
Funding Agency:
- National Institutes of Health
Biomolecular condensates (BMCs) are membrane-less subcellular domains that exhibit liquid-like features. BMCs form droplets that coalesce through liquid-liquid phase separation and dynamically exchange molecules with the surrounding environment. Examples of BMCs include the nucleolus, heterochromatin, stress granules, postsynaptic densities, and plasma membrane signaling clusters. Compartmentalization, concentration, or exclusion of molecules by BMCs can impact many cellular processes including regulation of gene expression, organization of subcellular structures, and regulation of receptor kinase signaling at membranes. Proteins prone to phase-separation are now known to have molecular features, such as intrinsically disordered regions (IDRs) or multivalent binding domains, while RNAs can be involved in BMC formation as well. There is mounting evidence that aberrant condensate formation by liquid-liquid phase separation is associated with human diseases, including cancer, infections, and neurodegeneration.
Nervous system BMCs have both nuclear and cytoplasmic functions. Some cytoplasmic BMC functions include inhibition of axon regeneration, synaptic transmission, transcription regulation through stress granules, maintenance of intrinsically disordered proteins (e.g. Tau and FUS) and clustering of calcium channels and neurotransmitter-containing synaptic vesicles. Some nuclear BMC functions include ribosome biogenesis (nucleolus), snRNP biogenesis (Cajal bodies), RNA splicing (nuclear speckles), histone gene synthesis (histone bodies), and regulation of chromatin structure and gene expression (heterochromatin formation).
Despite the emerging importance of BMCs in neuroscience, the tools we have to monitor and manipulate BMCs in vivo in the nervous system are in their infancy. While there has been some limited in vivo analysis using optogenetic and chemical methods, much of our current understanding of BMC physics and biology comes from in vitro studies and, to a lesser extent, studies in cultured cells. Establishment of new tools that exploit advances in imaging, optogenetic, chemogenetic, biophysical, single molecule, or other strategies would (1) enable in vivo BMC monitoring and manipulation and (2) provide much needed insight into BMC nervous system functions. This initiative would also support the development of high-throughput screening technologies to identify candidate molecules and regulators required for BMC formation and maintenance in the nervous system.
Research Objective. The objective of this NOFO is to support the development of innovative tools and/or technologies to monitor or manipulate BMCs in vivo and enable investigators to adopt these tools to answer outstanding questions in basic neuroscience. These tools or technologies have the potential to transform our understanding of the mechanistic role of BMCs in the human nervous system as well as advance our understanding of how condensate formation impacts cellular functions in nervous system health and disease. Recent studies indicate that small molecules that modulate condensate formation could serve as the foundation for the development of novel BMC-based therapeutics for nervous system diseases. It is anticipated that the tools developed by this initiative will be adopted by researchers to answer outstanding questions relevant to neurobiological processes or nervous system disorders of interest to the NIH Blueprint Neuroscience Institutes or Centers.
Responsiveness: Applications that are not responsive to this NOFO will not be reviewed. In order to be responsive to this NOFO, the applicant MUST:
- propose to develop tools or technologies to monitor or manipulate BMCs. Although applications may include an aim or sub-aim using disease-relevant perturbations for model validation and testing of assay utility, the primary focus should be on developing or improving technologies to study BMCs.
- propose to develop or test their tools or technology in a cellular, organismal, or other well justified system relevant to nervous system biological processes or disease. The ultimate goal of this NOFO is to support projects that go beyond what can be done with current technologies and move towards monitoring and manipulation of BMCs in the nervous systems (including both the central nervous system and peripheral nervous system) of living organisms. Applications proposing only in vitro or in silico experiments will not be responsive to this NOFO.
Other application considerations:
- This NOFO uses the high risk/high payoff R21 activity code. Preliminary technical or pilot data are NOT required or expected.
- It is anticipated that compelling projects will require interdisciplinary collaborations between individuals with expertise in biomolecular condensates and with significant knowledge of neuroscience processes. Some projects might also require expertise in optogenetics, chemogenetics, cell biology, biophysics, or other disciplines. Applicants are encouraged to establish such collaborations.
- Applicants are strongly encouraged to email the scientific contact if they have questions about this NOFO.
The combined budget for direct costs for the two year project period may not exceed $275,000. No more than $200,000 may be requested in any single year.
November 14, 2023
John Satterlee, Ph.D., National Institute on Drug Abuse (NIDA)
Telephone: 301-435-1020
Email: satterleej@nida.nih.gov