EXPIRED
July 22, 2021
New Date July 23, 2024 per NOT-AI-24-061 (Prior Date September 08, 2024)
PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
PA-20-195 – NIH Exploratory/Developmental Research Project Grant (Parent R21 Clinical Trial Not Allowed)
National Institute of Allergy and Infectious Diseases (NIAID)
This Notice of Special Interest (NOSI) supports research aimed at gaining a comprehensive understanding of the expression, function, and regulation of DEAD/H-box helicases in immune homeostasis, activation, and/or function.
Knowledge obtained from such studies may be applied to the design of improved vaccines and immunotherapies to combat pathogenic infections or treat/prevent immune-mediated diseases.
Background
DEAD/H-box helicases contain the conserved amino acid motifs Asp-Glu-Ala-Asp (DEAD) or Asp-Glu-Ala-His (DEAH). In humans, 42 DEAD-box and 16 DEAH-box helicases have been described. They are essential for RNA metabolism (e.g., RNA synthesis, processing, pre-mRNA splicing, modification, transport, translation, and turnover) and participate in almost every cellular process that involves RNA. In addition, individual DEAD/H-box helicases exhibit critical roles in pro- or anti-microbial responses. Various DEAD/H-box helicases (e.g., DHX15) in cells can serve as cytosolic sensors for viral RNAs and DNAs to initiate anti-viral responses; others have 1) a direct negative impact on viral replication by binding and inhibiting viral polymerase assembly or by participating in the degradation process of a viral RNA to restrict viral reproduction (e.g., inhibition of HBV by DDX3), or 2) a positive impact by suppressing IFN signaling pathway and, thus, enhancing viral infection. In conclusion, a better understanding of the role of DEAD/H-box (DDX) helicases in response to pathogens can aid in the development of novel therapeutics to combat infectious disease.
DEAD/H-box helicases also play an important role in inflammation, which may link to autoimmune and allergic diseases. It has been reported that DDX3X and DHX33 can interact with NLRP3 to drive inflammasome activation, whereas DHX9 can induce MyD88-dependent activation of NF-kB in plasmacytoid dendritic cells by sensing class B CpG motifs. NF-kB signaling also is modulated by DDX3, which promotes inflammation by enhancing the phosphorylation of the protein phosphatase PP2A.
While contributing to pro- or anti-microbial responses and inflammation, DEAD/H-box helicases also play a role in immune cell production, differentiation, composition, proliferation, and migration. For example, absence of DDX3X results in reduced hematopoiesis and abnormal composition of the leukocyte compartment of the bone marrow and spleen. Similarly, DDX46 contributes to the differentiation of hematopoietic stem cells (HSCs) into the various leukocyte lineages. DDX58 (RIG-I) can promote myelopoiesis via regulation of TRIM 25-dependent protein ISGylation. DDX18 is required for the proliferation of hematopoietic cells in zebrafish, and dysregulation of some DEAD/H-box helicases is linked to hematological malignancy, such as reduced DDX32 expression in acute lymphoblastic leukemias. Several DEAD/H-box helicases also have been implicated in cancer growth and metastasis.
Although DEAD/H-box helicases have broad functions in microbial infections, immune regulation, immune cell production, differentiation and composition of both myeloid and lymphoid cells, and cell cycle progression, their expression, function, and regulation remain poorly understood. A better characterization of DEAD/H-box helicases will provide foundational knowledge for understanding innate immune sensing, anti-microbial immunity, inflammation, and immune cell homeostasis, and for developing novel biomarkers and therapeutics for infectious and immune-mediated diseases.
Research Objectives
This NOSI encourages innovative research on the role of DEAD/H-box helicases in immune homeostasis and activation/function.
The scientific objectives of this NOSI include:
Applicants are encouraged to establish collaborations among immunologists, systems biologists, microbiologists, virologists, hematologists, and infectious disease experts to expand our knowledge of the function of DEAD/H-box helicases in the immune system.
Research areas of interest include, but are not limited to:
Application and Submission Information
This notice applies to due dates on or after October 5, 2021 and subsequent receipt dates through September 7, 2024,
Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement 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.
Scientific/Research Contact(s)
Qian “Joy” Liu, M.D., M.Sc.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-761-6621
Email: [email protected]