Showing 4 ideas for tag "ipf"

Goal 2: Reduce Human Disease

Pathobiology of Lung Fibrosis

End organ fibrosis accounts for up to 45% of deaths in developed countries. In particular, lung fibrosis is a devastating disease with poor prognosis. Despite development of two new drugs, their efficacy is still limited, highlighting the need to better understand the pathobiology that accounts for fibrotic disease progression in the presence and absence of acute exacerbation or infectious drivers.

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

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A better understanding of the pathogenesis of lung fibrosis may uncover new targets for therapy or identify biomarkers of disease progression.

Feasibility and challenges of addressing this CQ or CC

Approaches should include new and established animal models and experiments utilizing patient-based samples and novel mullti-center clinical trials. Ancillary studies should accompany any clinical trial to provide biologic insight into treatment responses and failures.

Name of idea submitter and other team members who worked on this idea Beth Moore

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Goal 2: Reduce Human Disease

How can we better understand regional tissue heterogeneity in lung disease?

Many lung diseases (IPF, COPD) are characterized by marked heterogeneity at the tissue level. Unfortunately, most of the tools we currently employ to understand lung disease are unable to elucidate the mechanisms that result in regional heterogeneity. Clinical studies and animal models, while invaluable, generally assume that all lung tissue is similarly affected based on the presence or absence of diagnostic criteria... more »

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

Details on the impact of addressing this CQ or CC

Emerging evidence suggests that diseases such as IPF and COPD have observable phenotypes at the cellular and tissue levels long before the disease is clinically apparent. Thus seemingly healthy patients may have some regions of the lung affected by the same pathophysiologic processes that drive clinically apparent disease. By changing the focus of investigation from the presence or absence of disease in a given patient to the presence of absence of disease in a given region, several advantages emerge: (1) pathophysiologic mechanisms may be investigated earlier in the natural history of a disease, when interventions are more likely to be of benefit; (2) early investigation favors the discovery of distinct disease subgroups that are masked in more severe disease; and (3) a single patient may provide multiple affected and unaffected disease regions, allowing him or her to serve as their own control. Recently, advances in next-generation sequencing have made it possible for the entire transcriptome of a single cell to be analyzed. It is reasonable to believe that in the next 10 years single cell epigenome, proteome, and metabolome profiling will become routine. However, it seems less obvious how these methodologies can be employed to better understand the drivers of regional differences in lung disease. While technically difficult, studies applying high-throughput technologies to the discovery of regional differences will be invaluable to our understanding of lung disease.

Feasibility and challenges of addressing this CQ or CC

To address this critical challenge, at least five technological hurdles will have to be addressed: (1) technologies such as laser capture microdissection which allow for the isolation or cells from specific areas of the lung will need to improve; (2) technologies allowing for culture of multiple cell types on a single artificial substrate (to allow for experimental manipulation of cellular “communities”) will need to emerge; (3) collaborative networks will need to emerge whereby datasets from multiple labs can be integrated; (4) bioinformatics and statistical methods capable of filtering massive “omics” data sets from multiple cell types will need to be refined; and (5) researchers with the skills necessary to distil large descriptive datasets into testable hypotheses will need to be trained. While these hurdles are great, they must be overcome in order to translate the promise of next-generation sequencing techniques into an improved understanding of the drivers of regional heterogeneity in lung disease.

Name of idea submitter and other team members who worked on this idea Bradley Richmond

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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... more »

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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