The lung is a richly innervated organ. Strong evidence, including recent findings from us, demonstrates that neuronal control plays central roles in basic lung response to the environment, including immune activity, as well as airway and vascular smooth muscle tone which impacts air conductance and pulmonary blood pressure, respectively. However, the full extent of how the nervous system affects lung function remains unclear, and little is known of the anatomical and molecular features of the neurons that innervate the lung. Here, we propose to use cutting-edge viral-based circuit tracing, single cell transcriptomic and haploid ES cell- based genome editing technologies to: 1) label lung-innervating neurons; 2) determine their localization and projection pattern; 3) generate knockin mouse lines that will lay the foundation for neuromodulation of lung function. Findings generated in mice will be tested in human biopsy samples to delineate conserved versus species-specific mechanisms. With the development of wireless, implantable devices, neuromodulatory therapy is on the horizon. Findings from this study will lay the necessary foundation for precise manipulation of organ function through the nervous system, and thus closely comply with the mission of the SPARC program.
Abnormalities in pulmonary immune response, airway conductance and pulmonary blood pressure are key features of lung-associated diseases such as asthma and pulmonary hypertension. Existing evidence suggest that the nervous system exerts key control in all critical lung functions. The goal of this study is to uncover foundational knowledge on the anatomical connectivity as well as molecular codes of the neural circuits that regulate these functions. Our findings will enable precise deployment of neuromodulatory devices as a new therapeutic arm for treating lung associated diseases.
| Sui, Pengfei; Wiesner, Darin L; Xu, Jinhao et al. (2018) Pulmonary neuroendocrine cells amplify allergic asthma responses. Science 360: |
| Verheyden, Jamie M; Sun, Xin (2017) Embryology meets molecular biology: Deciphering the apical ectodermal ridge. Dev Biol 429:387-390 |
