Chromosome 17q21, allergic inflammation, and remodeling

The focus of this proposal is on ORMDL3 a gene on chromosome 17q21, which has been highly linked to
human asthma in several genome wide association studies. As ORMDL3 is highly expressed in CD4+
cells, in this proposal we seek to determine how ORMDL3 influences CD4+ cell function, allergic
inflammation, and asthma. Although the linkage of chromosome 17q21 to asthma is very well established,
the biologic mechanism(s) underpinning this association in lung cells pertinent to the pathogenesis of
asthma is not as well understood and is the focus of this proposal. In addition as there are at least 9 genes
located in this region on chromosome 17q21 understanding the biology of each of these genes individually
is important to understanding how this region influences the development of asthma. As the SNP linking
ORMDL3 to asthma is associated with increased levels of ORMDL3 expression, we generated universal
ORMDL3 transgenic (TG) mice that express increased levels of human ORMDL3 (hORMDL3) and
demonstrated that they spontaneously (in the absence of allergen exposure) develop significantly
increased ASM and increased AHR, major features of asthma. In addition to this important baseline effect
of ORMDL3 in ASM on AHR, ORMDL3 also plays a significant role in enhancing Th2 responses and AHR
as demonstrated in our studies of allergen challenged universal hORMDL3 TG mice. Thus, the focus of
this proposal is to increase our understanding of how ORMDL3 expressed in CD4+ T lymphocytes
enhances Th2 responses to allergen challenge. In this grant proposal we propose to demonstrate that
CD4+ cells (mouse and human) expressing increased levels of ORMDL3 have enhanced Th2 responses
in vitro and in vivo to house dust mite (HDM) allergen, and using proteomic and RNAseq approaches plan
to identify downstream pathways in HDM tetramer positive CD4+ cells that mediate this ORMDL3 effect.
Targeted knockdown or overexpression of pathways identified to be downstream of ORMDL3 will
demonstrate their contribution to the function of CD4 cells. Finally, we are using single base editing to edit
SNPs linked to ORMDL3 to determine which SNPs functionally regulate levels of ORMDL3, Th2
cytokines, and downstream pathways of ORMDL3.

Grant Number: 5R01AI107779-10
NIH Institute/Center: NIH
Principal Investigator: DAVID BROIDE