R01HD109707

Targeting Cellular Senescence to Inhibit the Development and Progression of Ovarian Endometriomas - Ovarian endometriomas are deep endometriosis lesions on the ovary. Endometriomas are a unique form of endometriosis in that they do not respond to hormonal therapy and carry the highest risk of developing clear cell ovarian cancer.

There is an urgent need to determine the unique pathogenesis of endometriomas to improve the lives of women. As an alternative to retrograde menstruation, the induction theory of endometriosis posits that a substance induces an adult cell to transdifferentiate into endometriosis, although the inductive substances or the cells which transdifferentiate into endometriosis have yet to be identified.

AKA mice (ARID1AFLOX/FLOX; KRASFLOX-STOP-FLOX-G12D; AMHR2CRE) spontaneously and reproducibly develop large, cystic endometriomas that recapitulate human endometriomas at the histologic and molecular level. As the genetic recombination lies in the granulosa cells of the ovary, AKA endometriomas do not develop by retrograde menstruation. The AKA mouse model allows for the cellular and molecular interrogation of the paradigm-shifting induction theory of endometriosis using a rigorously reproducible and easily manipulatable model.

Transcriptomic analysis of AKA endometriomas revealed enrichment in cellular senescence genes. Cellular senescence is defined as a permanent cell cycle arrest. Senescent cells exhibit a senescence-associated secretory phenotype (SASP) and secrete high levels of pro-inflammatory molecules, similar to those found in the pelvic cavity of women with endometriosis. These results suggest that senescent cells in the AKA ovary secrete factors and induce endometriosis.

As for the cells induced, granulosa cells exhibit the ability to transdifferentiate, a developmental process by which fully differentiated cells change into different fully differentiated cells. The role of senescence in endometriomas is conceptually novel, and the ability of granulosa cells to transdifferentiate into endometriosis through senescence signaling is a new paradigm.

The central hypothesis is that the senescent microenvironment, mediated by ARID1A loss and oncogenic KRAS, is critical for developing endometriomas through induction and transdifferentiation of granulosa cells. The objective of Aim 1 is to characterize the unique transcriptomic profile of the senescent cells and the endometriotic microenvironment using spatial transcriptomics.

The objectives of Aim 2 are to identify the genetic changes (i.e., KRAS G12D) required for senescence in granulosa cells, validate the expression of the endometriosis SASP (from SA 1), and establish SASP-mediated endometriosis transdifferentiation using primary murine granulosa cell cultures and a soluble CRE recombinase.

The objectives of Aim 3 are to determine if senescence is essential for endometriosis and determine whether senotherapies restore ovarian function, fertility, and reduce endometrioma development and progression. Targeting senescence through senotherapies is critical to developing non-hormonal therapies, an urgent unmet need for endometriosis.

Trustees Of Indiana University

NOT APPLICABLE

93.393 - Cancer Cause and Prevention Research

National Institute of Child Health and Human Development (NICHD) [HHS - NIH]

Indianapolis, Indiana 462025188 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 384% from $657,190 to $3,180,942.