August 14, 2023
National Institute on Aging (NIA)
This Notice of Special Interest (NOSI) invites applications to continue the investigation of biomolecular condensates in aging and Alzheimer's Disease (AD) and AD-related Dementias (ADRD).
Protein aggregation has been a long-standing hallmark of neurodegenerative diseases, such as AD/ADRD. For these conditions, there are a wide variety of proteins implicated in aggregation and disease, including such proteins as tau, TAR DNA-binding protein 43 (TDP-43), and fused-in-sarcoma (FUS). A common link between these proteins is they all undergo liquid-liquid phase transitions (LLPS) to form biomolecular condensates (BMCs) under normal biological conditions to function properly. While classical organelles are surrounded by phospholipid bilayers, BMCs are described as membraneless organelles where proteins, ribonucleic acid (RNA), deoxyribonucleic acid (DNA), and other cellular molecules are brought into close proximity to promote their interactions and to enhance their bioreactivity. Beyond enhancing protein function in the cytoplasm, BMCs are also found within the nucleus and play a role in regulating gene expression. Formation and regulation of BMCs are highly dependent on multiple cellular components, including, but not limited to, protein and osmolyte concentration, osmotic and oxidative stress, temperature, and adenosine triphosphate (ATP) levels.
Another factor that can influence BMC formation is the nuclear pore complex (NPC), which can transport proteins and nucleic acids in and out of the nucleus. Emerging evidence has created a unique nexus between nuclear BMC function, cytoplasmic BMC function, the nuclear pore complex, and how aging and AD/ADRD may alter these normal functions. Many proteins that aggregate in AD/ADRD undergo transport in and out of the nucleus via the NPC, and the NPC has been shown to help disaggregate these proteins. Additionally, as aging occurs the NPC functions less efficiently, leading to improper transport in and out of the nucleus, which could lead to mislocalization of BMC associated proteins. Aging and cellular stress have also been linked to aberrant BMC formation and disease onset.
Despite this growing evidence, there are still basic scientific questions to answer related to how BMC formation is regulated within the cell and what makes certain cells or proteins more susceptible to aberrant BMC activity. For example, what types of modifications drive tau BMC formation, and what changes occur to promote tau aggregation in AD? Furthermore, do proteins form the same type of BMCs in different cell types or are there cell-specific conditions that promote or dissolve BMC formation that may impact aging or disease onset/progression? How do changes to NPC function impact BMC formation or dissolution in specific cell types? This NOSI aims to provide researchers an opportunity to continue generating data on how different cells ordisease conditions may impact BMC formation and function, either cytoplasmic or nuclear, and what role the NPC may play. There are emerging tools being developed to better study BMCs in cells and in vivo, so it is a prime time to bring experts using these tools into the aging and AD/ADRD fields to stimulate research on possible mechanisms driving disease.
This NOSI invites research that investigates cell-specific mechanisms of BMC formation and function, investigate the role the NPC plays in regulating BMC formation and cell specific impact, and exploit existing tools or develop new tools to study the neurobiology of BMCs in aging and AD/ADRD.
Examples of topic areas responsive to this NOSI include, but are not limited to, the following:
Applicants should briefly describe how their proposed studies will significantly improve the scientific community's understanding of how BMCs impact different cell types and how alterations to BMC formation and function can alter cellular biology in aging and AD/ADRD.
It is anticipated that compelling projects will require multidisciplinary collaborations between individuals with expertise in biomolecular condensates and with significant knowledge of neurobiology of aging and AD/ADRD. Applicants are encouraged to establish such collaborations in these areas, as well as other disciplines as needed.
This notice applies to due dates on or after October 5, 2023 and subsequent receipt dates through November 13, 2024
Submit applications for this initiative using one of the following notice of funding opportunities (NOFOs) or any reissues of these announcements through the expiration date of this notice.
All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:
Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.
Please direct all inquiries to the contacts in Section VII of the listed notice of funding opportunity with the following additions/substitutions: