Grantor: Croatian Science Foundation
Grantor’s website: www.hrzz.hr
Total funding: 1,000,000.00 HRK
Principal investigator: Prof. Biserka Mulac Jeričević, PhD
Research team:
- Jan J. Brosens, MD, PhD
- Prof. Gordan Gulan, MD, PhD
- Zdravko Jotanović, MD, PhD
- Prof. Neda Smiljan Severinski, MD, PhD
- Prof. Jagoda Ravlić-Gulan, MD, PhD
- Sandra Šućurović, PhD
- Tamara Nikolić
Brief description:
Progesterone (P) is an indispensable regulator of female reproductive function, but also has an important role in non-reproductive tissues. Aberrant P signaling has been associated with reproductive conditions, cancer, metabolic disorders, cardiovascular defects, and neurological defects. In humans and mice the physiological effects of P are mediated by two intracellular receptors, termed PR-A and PR-B, expressed in subset of cells in target tissues. PR-A and PR-B isoforms are transcribed from a single gene by alternative promoter usage. PR-A (94 kD) isoform differ from PR-B (120 kD) by lacking 164 amino acids at the N terminus. Analyses to date have shown that PR-A and PR-B mediate mostly distinct but partially overlapping reproductive tissue selective physiological responses to P. The overall objective of this research is to establish the selective physiological roles of each of the individual PR isoforms in their natural physiological context. For this research we will use a genetically modified mouse in which gene targeting was used to knockout expression of either the PR-A or PR-B isoform in mice. The specific aims of this application are as follows: 1. To examine the isoform-selective molecular mechanisms by which PR-A and PR-B differentially regulate uterine epithelial proliferation, uterine receptivity and stromal decidualization. 2. To examine the selective contributions of the PR-A and PR-B isoforms to the P-dependent immunomodulatory activity during early pregnancy. 3. To identify progesterone-regulated genes in musculoskeletal tissue using a genetically altered mouse models lacking progesterone receptors. 4. To determine whether differential signaling pathways of PR isoforms are conserved from rodent to human. It is expected that this research will contribute to understanding the molecular mechanisms of P in reproductive tissues and musculoskeletal and could lead to new strategies for disease prevention and treatment.