Notice of Special Interest (NOSI): Studies of Cellular/Molecular Pathobiological Mechanisms of Lung Diseases Using Human 3-Dimensional Cellular Systems (R01)
Notice Number:

Key Dates

Release Date:

July 5, 2022

First Available Due Date:
October 05, 2022
Expiration Date:
September 08, 2025

Related Announcements

PA-20-185 (NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

PA-20-183- NIH Research Project Grant (Parent R01 Clinical Trial Required)

Issued by

National Heart, Lung, and Blood Institute (NHLBI)



The purpose of this NOSI is to promote research characterizing the pathobiological processes and mechanisms that drive the onset and progression of lung diseases at a molecular/cellular level, providing a systems-level understanding by studying experimental systems with cellular heterogeneity and 3-D architecture. It is expected that projects supported by this NOSI will utilize ex vivo preparations (e.g., thin human lung slices) or 3-D multi-cellular in vitro systems (e.g., organoids) of human lung cells and will employ state-of-art multi-omics measures (e.g., spatial or single cell/nucleus omics) to better understand specific pathobiological processes in systems of interacting cell types.


Lung diseases are often diagnosed at an advanced stage, when treatment options become very limited. A major barrier to early diagnosis and targeted therapy is the lack of detailed understanding of complex pathobiological processes. Lung cellular heterogeneity, coupled with heterogeneity of molecular mechanisms, produces a wide range of disease endotypes and clinical outcomes. Research conducted at the whole tissue level cannot resolve the heterogeneity of lung pathobiology. There is a compelling need to longitudinally map different lung cell types/states and their molecular phenotypes to better understand lung resilience and disease onset and progress. A major obstacle to this research is selection of an appropriate experimental systems. Fortunately, there has been important progress in developing physiologically more relevant, yet amenable, experimental systems, such as human 3-D multi-cellular systems (e.g., lung organoids, lung-on-chips, bioprinter lungs, ex vivo perfused lungs, or precision-cut lung slices), which are useful for longitudinal mechanistic studies and testing therapeutic strategies. In addition, advances in omics technologies allow high-throughput unbiased characterization of the biological diversity and complexity of lung cell types/states and molecular phenotypes at in-situ spatial levels. Though organoids composed of only one cell type have been widely used by research community, few studies have integrated multiple experimental approaches, including human studies, state-of-art 3-D heterogenous multi-cellular systems that mimic the cellular complexity of the human lung, disease modeling, and single cell multi-omics, to gain a systems level understanding of pathobiology and pathogenesis and drug effects for lung diseases.

Selected Research Examples:

The goal of this NOSI is to solicit ambitious research by combining four capabilities: human studies, 3D multi-cellular systems, disease modeling, and single cell multi-omics to gain novel understanding how known pathobiological processes of lung diseases operate, thereby identifying molecular readouts that can reasonably be used to screen compounds for their potential as preventive or therapeutic drugs. This NOSI encourages multi-PI studies with one PI in pulmonary research and another PI who has developed or used 3D systems and/or single cell or spatial omics and research taking advantage of banked human iPSC lines. It will support research projects exemplified by, but not limited to, the following:

  • Projects that use spatial omics in human precision-cut lung slices to map cellular identity and location-specific transcriptomic landscape of pathobiological processes (e.g., inflammation, cell death, fibrosis, tissue remodeling, premature-aging, progenitor cell dysfunction, etc.)
  • Single cell omics characterization of susceptibility, resilience, or recovery from injury in 3D systems that involve multiple, interacting human lung cells
  • Studies using human iPSC-derived lung organoids that explore how induced genetic manipulations in one cell type affect transcriptomic and proteomic profiles in other cell types and identify key proteins responsible for cellular communications
  • Investigations of the impact of specific environmental factors (e.g., smoking, toxin, nutrient, etc.) in injury, resilience, differentiation, and remodeling of different cell types in human lung organoids
  • Testing of whether co-culture with additional cells (e.g., macrophages) modulates self-renew and differentiation of lung progenitors (e.g., basal cells or endothelial progenitor cells) and their interactions with structural cells in human lung organoids
  • Organoid or tissue slice studies of cell-type specific responses to pulmonary drugs that show promise as disease-modifying therapies
  • High throughput screening of candidate drugs for their ability to reverse disease-related, cell type-specific transcriptional abnormalities in human lung organoid systems
  • Studies of synchronization of circadian function in systems involving multiple cell types
  • Studies using lung organoids derived from iPSC of smokers with or without COPD to understand cellular/molecular mechanisms for lung resilience.
  • Research using single cell multi-omics and human iPSC-derived lung-on-a chip with air-liquid interphase culture to test infectivity of different variants of SARS-Cov2 viruses and test drug treatments or determine cellular/molecular mechanisms for host resilience and disease progression.
  • Research using human multi-cellular 3D in vitro systems and single cell multi-omics to study pathobiological mechanisms of Post-Acute Sequelae of SARS-CoV-2 Infection.

Application and Submission Information

This notice applies to due dates on or after September 25, 2022 and subsequent receipt dates through September 7, 2025.

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.

  •  PA-20-185- NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
  • PA-20-183 - NIH Research Project Grant (Parent R01 Clinical Trial Required)

NHLBI will accept only mechanistic studies that meet the NIH definition of a clinical trial (see NOT-HL-19-690) in response to PA-20-183 - NIH Research Project Grant (Parent R01 Clinical Trial Required) and its reissues. For additional information, please see the NHLBI Policy Regarding Submission of Clinical Trial Applications (Notice NOT-HL-18-611) to identify the most appropriate FOA.

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

  • For funding consideration, applicants must include “NOT-HL-22-030” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

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 funding opportunity announcements with the following additions/substitutions:

Scientific/Research Contact(s)

Qing Lu, Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Division of Lung Diseases
Telephone: 301-480-9158


Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Financial/Grants Management Contact(s)

Anthony Agresti
National Heart, Lung, and Blood Institute (NHLBI)

Telephone: 301-827-8014