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CU-Anschutz School of Medicine Website
Our laboratory is part of the Division of Reproductive Sciences and the Division of Reproductive Endocrinology within the Department of Obstetrics and Gynecology at the University of Colorado Anchutz Medical Campus in Aurora, Colorado. Our overall goal is to improve the health and well-being of women. In one central project, we are investigating mechanisms that lead to accelerated female reproductive aging, which can manifest when ovarian function ceases early in life relative to the expected time of menopause. Our group is focused on mechanisms that control primordial follicle growth activation (PFGA). The reason for this focus is that the rate of loss of the primordial reserve of follicles determines whether a woman will experience a 'normal' duration of ovarian function, or instead, face primary ovarian insufficiency (POI) where ovarian function ceases before the age of 40.
Approximately 1 in 250 women will experience POI prior to age 35, and 1 in 100 prior to age 40, An additional 5% of women experience ovarian failure between 40 and 45 years, outside the definition of POI. In combination, the cost of POI to individuals and to society is extraordinarily high. If afflicted with POI, women can face decades of increased risk for these problems of aging and their treatment limitations. Further characterizing the mechanism(s) that drive PFGA and thus ovarian aging will fill major gaps in our understanding of this critical biological process. This may lead to future interventions to slow ovarian aging and improve the health of women.
Lab Theme Highlight, Winter 2023: How random is ovarian aging?
November, 2022: Our work investigating ovarian aging using mathematical modeling continues, and we wrote up a blog post for a more general audience here. The post puts our recent work into context with several excellent "historical" publications, and argues that ovarian aging may arise as an "emergent behavior" that results from the action of individual primordial ovarian follicles. Is the mammalian ovary "a non-trivial, emergent, self-organizing system, with limited adaptive capacity?" Publications in this area are discussed below:
Our collaboration with Dr. Jay Emerson of the Yale University Department of Statistics and Data Science, and Dr. Sean Lawley of the Department of Mathematics at the University of Utah continues! We have followed up on our first manuscript on the topic ("Recapitulating Human Ovarian Aging Using Random Walks" in PeerJ with a second paper, online February 16, 2002 in lab favorite journal Biology of Reproduction. The new paper addresses the interesting question of "why there is an 'oversupply' of human ovarian follicles in newborn girls?" It is very well known that newborn girls can have upwards of a million primordial follicles, but of that large number, only a few thousand should be needed to keep adult ovarian function going, and only around 500 will likely ever ovulate an egg. If the mechanism that controls primordial follicle growth activation is stochastic, or "random," the large numbers of follicles early in life can keep a steady supply of growing follicles for decades! Experimental data is needed to further probe this question but the mathematical analysis is a great first step.
For both of these papers, we drew upon our prior work that identified the Integrated Stress Response pathway as a regulator of the cell cycle in ovarian follicles, and modeled dormant primordial ovarian follicles as undergoing random walks versus a threshold of growth. Remarkably, simulating hundreds of thousands of primordial follicles in this way recapitulates both the known pattern of follicle loss during aging, and also, the distribution that women undergo menopause. There are still new insights coming in the pipeline with implications for ovarian physiology and perhaps, with some clinical implications for ovarian aging! EASTER EGG: if you send an email to:
johnsonlab AT proton DOT me
with "SIM" in the subject line, we'll send you unique results of a random walk simulation of ovarian aging, using the R code developed for our paper, and run just for you.
Next, in a collaborative project with members of the Division of Urogynecology and Pelvic Floor Surgery, we are also investigating mechanisms that lead to the degeneration of pelvic floor support structures. We are focused on the cell and tissue biology of pelvic floor ligaments, as well as their biomechanical properties. Our goals here are to uncover preventative strategies to lessen the incidence of pelvic floor organ prolapse, and also reduce the recurrence of the condition.
Black History Month 2023, Interview with SSR Reflects
Last, it was a pleasure to visit with Dr. Dawit Tesfaye of Colorado State University to discuss my background and some of my (Josh's) experiences that led me here. That interview transcript is provided here.