Addressing this critical challenge will enable scientists and clinicians to move beyond the identification of singular risk factors for obesity to develop a holistic approach to prevention and treatment of this critical health problem.

The molecular technology, environmental monitoring technology, analytic and bioinformatics infrastructure are sufficiently developed to generate the necessary data and analyze disparate data types within the larger systems biology framework.

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.

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.

Once such study is established, it can be used as a wellness model/control for many diseases and conditions. The longer we have the study, more useful it will become. This can help us to change or optimize our health care model, from treating diseases to maintain wellness.

This can be quite feasible as there are many frequent and long term donors. They care about others’ health as well as their own health. They are also very willing to support research. Follow-up can start from early adulthood.

With funding support this can be achieved.

Chest CT scans provide anatomical information on disease pattern and severity that cannot be readily obtained otherwise. These imaging studies could be essential in reclassifying chronic lung diseases more effectively and in assessing disease progression more accurately.

The increasing use of chest CT scans for lung cancer screening will provide a large number of imaging studies that could transform pulmonary research in multiple chronic lung diseases. However, the images will need to be appropriately collected and analyzed.

High quality T4 research methods and metrics are needed to move the field of T4 translation research forward while linking large data sets from different sources.

Demand for high quality methods, metric and evaluation of T4 translation research interest is growing and needs to be addressed immediately to move the field forward.
Recent IOM/NRC studies recommended that the NIH and other research funding agencies support the development of more refined analytic methods and study designs for cross-national health research. These methods should include innovative study designs, creative uses of existing data, and novel analytical approaches to better elucidate the complex causal pathways. The T4 field has some specific metrics including acceptability, reach, adoption, appropriateness, feasibility, fidelity, cost, penetration, and sustainability, each with its standard measurement approach. In addition to a rigorous study design, including these metrics along with population level impact direct measures (e.g., morbidity, mortality) and intermediate measures (e.g. blood pressure reduction) will be critical to assess what has been accomplished and to define success. Finally, measuring the overall impact of new knowledge generated from T4 research is challenging because publication bibliometrics of high impact scholarly journals may not fully capture it.

Could restore lost or diminished organ function

Extensive research infrastructure already exists and durability and quality of beneficial effects has continued to increase over time, although incrementally. Field is poised for a breakthrough with the right spark funding.
Cell-based therapies, demonstrated with a wide range of cell types, have shown glimmers of promise in HLB applications, such as improved functional recovery, reduced scar formation, and beneficial effects up to 6 months. However, transplanted cells have poor retention, minimal long-term survival, and the mechanism-of-action is unclear.

The challenge is to stimulate new hypotheses on the mechanism-of-action in order to achieve long-term benefits, and then to support definitive confirmatory studies. Funding already exists, but the main spark might come from encouraging other disciplines to get involved.