Friday, January 28, 2022
1/28/2022
Gestational diabetes (GDM), or hyperglycemia that first manifests during pregnancy, worsens pregnancy outcomes and long-term health risks for both a mother and her offspring. As with all types of diabetes, a relative insufficiency of functional pancreatic ß-cells is a fundamental defect contributing to GDM. Normally, ß-cells adapt to the metabolic challenges of pregnancy by expanding ß-cell mass. This expanded mass regresses in the postpartum period. Thus, pregnancy is a unique physiologic condition that occurs in a fully-developed adult and requires rapid, dynamic changes in ß-cell mass. Unfortunately, the mechanisms of normal gestational ß-cell adaptation and the defects underlying GDM are poorly understood. Our long-term goal is to understand the mechanisms regulating ß-cell proliferation and mass during pregnancy, in order to leverage that knowledge for therapeutic expansion of ß-cells in all types of diabetes. Building on our work establishing that loss of prolactin receptor (PRLR) signaling in ß-cells results in GDM, we recently identified novel PRLR differentially expressed genes (PRLR-DEGs) and key transcriptional regulators of PRLR-DEG expression. The objective of this grant is to precisely define how PRLR regulates ß-cell gene expression during pregnancy and the postpartum period. We propose the central hypothesis that PRLR signaling orchestrates an anticipatory transcriptional program of ß-cell mass expansion during gestation and survival of adequate ß-cell mass during postpartum regression. We will test this hypothesis with the following Specific Aims: (1) elucidate transcriptional mechanisms regulating PRLR-DEGs within ß-cells during pregnancy. To do so, we will use ChIP-seq and ATAC-seq to examine how PRLR-DEGs are regulated in mouse and human islets during pregnancy or in response to prolactin stimulation. In Aim (2) we will define PRLR signaling-dependent and -independent ß-cell subpopulations during pregnancy using single-cell RNA sequencing, lineage tracing and colocalization studies. For Aim (3) we will identify mechanisms of ß-cell survival during ß-cell mass regression in the early postpartum period through pulse-chase labeling and lineage tracing of ß-cells that proliferated during pregnancy, as well as examine how inducible loss of PRLR specifically within the postpartum period affects ß-cell mass. Together, results from these studies will reveal transcriptional mechanisms downstream of PRLR and illuminate unique aspects of gestational proliferation (Aim 1), define ß-cell subpopulations spatially and temporally across pregnancy (Aim 2), and establish a new role for PRLR signaling in regulation of ß-cells postpartum (Aim 3). Our research is significant because these findings would clarify mechanisms of gestational ß-cell adaptation and expand our understanding of how PRLR activation regulates transcription. At a fundamental level, these studies will expand our understanding of the mechanisms regulating dynamic changes in ß-cell mass, which may identify novel strategies to promote ß-cell expansion for therapeutic purposes.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
