Bivalent IRE1A regulation of epithelial cell fate and function in muco-obstructive lung disease

The National Heart, Lung, and Blood Institute awarded The Regents of the University of California, San Francisco $158,696 on December 1, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to support postdoctoral research training focused on IRE1A-mediated mechanisms in obstructive lung disease pathogenesis.

The award funds the training of Dr. Nathaniel Harder in studying how IRE1A signaling regulates epithelial cell fate and function in lung disease. Dr. Harder, working under the mentorship of Drs. David Erle and Vincent Auyeung at UCSF, will investigate two primary research aims. Aim 1 tests the hypothesis that XBP1, activated by IRE1A, acts synergistically with the transcription factor FOXA3 to drive goblet cell metaplasia—a pathology in certain obstructive lung diseases—through analysis of XBP1 binding to FOXA3 enhancer regions, co-regulation of genes through collaborative enhancer binding, and direct molecular interactions between the two factors. Aim 2 tests whether regulated IRE1A-dependent decay (RIDD) controls ciliated cell differentiation and function by examining lung epithelial ciliated cell function, IRE1A-mediated degradation of DNAH5 RNA, and related pathway mechanisms. The research leverages advanced models of human biology, computational biology, and bioinformatics to elucidate ER stress pathway mechanisms.

Period of performance runs from December 1, 2026, through June 30, 2029, with work performed in San Francisco, California. This is a Project Grant, a research training award vehicle under NHLBI's competitive research training grant portfolio.

Abstract

The work proposed in this fellowship application focuses on the training of DR. Nathaniel harder in studying the mechanisms of IRE1Α-mediated obstructive lung disease pathogenesis. The goals include leveraging advanced models of human biology and disease, and computational biology and bioinformatics to elucidate ER stress pathway mechanisms by which lung epithelial cell fate and function are altered. With the support and guidance of DRS. David erle and vincent auyeung at ucsf, the proposed research aims will investigate the bivalent mechanisms of action of IRE1Α, regulation of both XBP1'S transcriptional activity and regulated IRE1Α-dependent decay (RIDD), through two distinct aims. Aim 1 will test the hypothesis that XBP1 acts both on and synergistically with the goblet cell master transcription factor FOXA3. When activated by IRE1Α, XBP1 can alter basal fate and lead to goblet cell metaplasia, a key pathology of certain obstructive lung diseases. Preliminary data analyzed by DR. Harder has demonstrated potential regulatory coordination between XBP1 and FOXA3 which will be investigated though analysis of XBP1 binding to the enhancer region of FOXA3 (aim 1.1), the CO-regulation of genes through collaborative enhancer binding of XBP1 and FOXA3 (aim 1.2), and the molecular interactions of the two transcription factors (aim 1.3). Aim 2 will test the hypothesis that RIDD controls ciliated cell differentiation and function. In cells treated with an inhibitor of IRE1Α selective for RIDD, a gene related to ciliated cell fate was increased, suggesting a relationship between the RNA degradation associated with RIDD and ciliated cells. This relationship will be investigated through the analysis of lung epithelial ciliated cell function (aim 2.1), ciliated cell function (aim 2.2), IRE1Α-mediated degradation of DNAH5 RNA (aim 2.3), and elucidation of pathways of ciliated cell differentiation altered by RIDD degradation (aim 2.4). Completion of these research aims is expected to lead to the identification of targetable therapeutic pathways that could restore a healthy homeostatic balance in lung epithelial cell population and function. These aims will derive additional hypotheses for future development as an independent career scientist. To ensure the training develops critical characteristics to support DR. Harder's career, training will include interaction with the scientific community through presentations and writing, and the development of laboratory leadership skills while upholding the rigor and ethics essential for crucial as a scientist. The ruth L. Kirschstein national research service award individual postdoctoral fellowship will facilitate DR. Harder's evolution into an independent scientist while building his collaborative network of research professionals essential for future success.