Knock out of the gene encoding the ?-7 nicotinic acetylcholine receptor (?7nAChR) has established that ?7nAChR is an absolute requirement for the anti-inflammatory activity of the vagus nerve. In humans however, there exists a naturally occurring human-specific mechanism that mimics gene knock down of ?7nAChR. In this process, the human specific gene CHRFAM7A is a dominant negative inhibitor of ?7nAchR. Because CHRFAM7 expression varies from up to 200 fold between individuals, it is ideally suited to gauge the anti-inflammatory activity of the human vagus nerve. Here we hypothesize that transgenic expression of the human CHRFAM7A gene in mouse will lead to a phenotype similar to the ?7nAchR knockout mouse and result in a functional ?human phenotype? based on the expression of CHRFAM7A. To this end, we will (1) determine the biological consequence of CHRFAM7A expression in monocytes/macrophage cell lines, (2) characterize the effects of CHRFAM7A expression on ?7nAchR signaling in primary human macrophages and (3) compare the biological consequences of introducing the CHRFAM7A gene into mice. At the conclusion of this research project we will have (1) established the biological significance of CHRFAM7A to inflammatory signaling by the ?7nAchR, (2) determined the consequence of CHRFAM7A expression in vivo, and (3) established whether CHRFAM7A has the ability to alter the anti-inflammatory effects of vagus nerve signaling.

Public Health Relevance

CHRFAM7A is a human-specific gene that modulates ?-7 nicotinic acetylcholine receptor (?7nAChR)-mediated anti-inflammatory signaling that is an absolute requirement for the anti-inflammatory activity of the vagus nerve. Here we hypothesize that transgenic expression of the human CHRFAM7A gene in mouse will lead to a phenotype similar to the ?7nAchR knockout mouse. In this proposal, we will (1) characterize the effects of CHRFAM7A expression on ?7nAchR-mediated inflammatory signaling using differentiated THP1 cells, (2) characterize the effects of CHRFAM7A expression on ?7nAchR signaling in normal human macrophages and (3) compare the biological consequences of introducing the CHRFAM7A gene into mice with ?7nAchR gene knock out.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM121530-03
Application #
9666928
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Zhao, Xiaoli
Project Start
2017-04-01
Project End
2022-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Surgery
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093