Goal 2: Reduce Human Disease

UNDERSTANDING PROGRESSIVE FIBROTIC DISEASES TO IDENTIFY NEW THERAPEUTIC TARGETS

Our understanding of the factors driving IPF fibrotic progression remain incompletely understood. To develop effective therapies that arrest and reverse the fibrotic process, we must first identify the critical factors driving the spread of fibrosis. Fibroblastic foci, the sentinel morphologic lesion of IPF, are found at the advancing edge of fibrosis. Fibroblastic foci can be conceptualized as a fibrotic niche. The interplay among the cells in the fibrotic niche with environmental factors such as extracellular matrix composition, topography and stiffness in addition to other factors are likely critical factors driving fibrotic progression. Unfortunately the composition of the fibroblastic focus is incompletely defined.

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Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Technologically advanced descriptive studies to create a comprehensive fibroblastic focus atlas are a necessary first step to understand fibrotic progression. The atlas will include: 1) The identification and number of each the cell type in the focus and their interplay. There is considerable heterogeneity among the mesenchymal cells and inflammatory cells within the focus and innovative single cell OMICs technology will be required to define disease-relevant subpopulations of each cell type within the focus. This work requires laser caption microdissection, immunohisotchemical and in situ hybridization techniques to map the location of various cell types within the fibroblastic focus. 2) Extracellular matrix composition and mechanical properties. Currently it is unclear whether the fibroblastic focus is topographically polarized. For example, it is conceivable that the focus may be polarized with cell-dense regions consisting of various cell types in a provisional/wound-like matrix juxtaposed to less cellular regions consisting of more mature mesenchymal cells in a collagen rich matrix. 3) Cytokine levels and oxygen tension. There is a large and expanding literature in several biomedical disciplines that each of these characteristics matter; influencing differentiation, proliferation, metabolism, and migration. Lacking all of these data, it is not surprising that IPF has been such a difficult problem to solve.

Feasibility and challenges of addressing this CQ or CC :

Since these will be highly innovative, yet descriptive – funding them through investigator initiated awards reviewed by standing study section is not feasible. They will employ novel emerging techniques including single cell RNA sequencing and single cell mass cytometry to identify heterogeneous cell populations, state of the art proteomic techniques to define matrix composition and cytokine levels within the fibroblastic focus, and atomic force microscopy to map stiffness across the fibroblastic focus. When considering applications, an RFA mechanism makes sense (perhaps a U-series granting mechanism) where the standard criteria are used for review, but innovation accounts for 75% of the total priority score. The idea is that the reviewers’ discussion and score will be heavily weighted towards innovation, i.e. really new ideas or approaches with less emphasis on a detailed critique of the methods to be employed, and the impact of the project in advancing knowledge. Therefore, convening a Special Emphasis Panel (SEP) that is instructed to identify the most highly innovative, high impact projects would be ideal.

Name of idea submitter and other team members who worked on this idea : Craig Henke and Peter Bitterman

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Idea No. 683