We are grateful to the sponsors of our research. Funded research projects in the Duncan Lab include:
Oocyte genomic instability as a driver of the aging ovarian innate immune response
The proposed research addresses the molecular origins of female reproductive aging, which impacts fertility, endocrine function, and overall health. We will test the hypothesis that ovarian aging is fueled by damaged DNA inthe oocyte which stimulates an inflammatory response in the surrounding somatic follicular cells that is further amplified by spatial cues within the broader microenvironment. This project provides a novel paradigm for female reproductive aging, a major reproductive transition, and thus aligns with NICHD priorities. This is a joint project between Dr. Francesca Duncan (contact PI) and Dr. Jennifer Gerton (co-PI) (R01HD105752).
Senescent cell mapping, identification and validation for human somatic and reproductive tissues
Cellular senescence is a multi-faceted cell fate that arrests cell proliferation and activates the synthesis and secretion of numerous cytokines, chemokines, growth factors, proteases and lipids, termed the Senescence Associated Secretory Phenotype (SASP). The SASP can influence tissue microenvironments, locally and distally, and thus senescent cells can strongly affect tissue function. Senescent cells (SnCs) increase with age in most vertebrate organisms, including mice and humans, and it is increasingly clear through both genetic and pharmacological manipulations that they can drive a growing list of age-related pathologies, ranging from neurodegeneration to cancer. At present, there are no invariant biomarkers of SnCs and the molecular characteristics of SnCs are remarkably heterogeneous and variable, depending on cell and tissue type, microenvironment, senescence inducer, and timing. Our overall goal is to determine, molecularly and spatially, when and where senescent cells occur in humans, and also how their patterns of gene expression and SASPs vary with tissue physiology and age in three human tissues: ovary, breast and skeletal muscle and three biofluids: follicular fluid, plasma and urine. This work is part of the Common Fund’s Cellular Senescence Network (SenNet) and is a collaboration with Dr. Judy Campisi (PD/PI), Dr. Birgit Schilling (PD/PI), Dr. Chris Benz (Biospecimen Core co-PI) and Dr. Mary Ellen Pavone (subcontract co-I) (U54AG075932).
Evaluating diverse technologies for detecting and validating senescent cells in vivo
Cellular senescence is a multi-faceted cell fate that arrests cell proliferation, essentially irreversibly, and activates the production and secretion of pro-inflammatory cytokines, chemokines, growth factors, proteases and lipids, termed the Senescence Associated Secretory Phenotype (SASP). The SASP can influence tissue microenvironments, and thus senescent cells can strongly affect tissue function and likely the systemic milieu. Senescent cells increase with age and can drive a growing list of age-related pathologies, ranging from neurodegeneration to cancer, in part through the SASP. There is increasing evidence that there are no universal markers for senescent cells. Instead, senescent cells, while sharing certain characteristics and biomarkers, are remarkably heterogeneous, varying in characteristics with genotype, cell and tissue type, senescence inducer, tissue (and cell culture) microenvironment, and chronology (time after initial senescence induction). While some of the more commonly employed senescence markers have utility in superficially identifying senescent cells de novo, the onus remains on the investigator to demonstrate why a cell should be considered senescent, rather than relying on historical markers such as p16INK4a or p21Cip1. Thus, new technologies designed to identify novel senescent cells and phenotypes are necessary that will require validation both in culture and in tissue. The ultimate goal of this proposal is to develop new technologies to map senescent signatures back to intact human tissue. Specifically, we will develop a microphysiologic ex vivo tissue-on-a-chip to model ovarian senescence and human tissue-tissue interactions via the SASP. This project is part of the Common Fund’s Cellular Senescence Network (SenNet) and is a collaboration with Dr. Simon Melov (PD/PI), Dr. Mary Ellen Pavone (subcontract co-I), and Dr. Julie Kim (subcontract co-I) (1UG3CA268105).
Accelerated aging of the ovarian matrisome as a mechanism of racial disparities in ovarian cancer
Ovarian cancer is the fifth leading cause of cancer deaths in the US and disproportionately affects Non-Hispanic Black (NHB) women. Even among patients with equal access to care, the all-cause mortality rate of NHB ovarian cancer patients is 1.3 times higher than non-Hispanic White (NHW) counterparts. This project will provide unprecedented insight into whether differences exist in the aging of the ovarian ECM between NHB and NHW women and how differential ovarian aging may promote increased ovarian cancer pathogenesis. Funding source: H Foundation Core Usage Pilot Project Award.
FSH Glycoforms and Ovarian Signaling Pathways
Aging in women is associated with diminished ovarian responses to follicle-stimulating hormone (FSH) as well as the oocyte quality. Our studies using novel genetic models expressing different age-specific FSH glycoforms will not only provide mechanistic insights but unequivocally test the role of FSH-mediated signaling pathways in vivo in the ovary which produces estrogen and eggs. Thus, our studies may lead to developing novel FSH-based therapies to preserve and enhance ovarian function in women. This is a joint project between Dr. T. Rajendra Kumar (PI) and Dr. Francesca Duncan (co-I) (R01HD103384).
Ovarian Contraceptive Discovery Initiative
Enabling Reproductive Intentions
Seeking novel, female-targeted, non-hormonal contraceptives is a key aspiration for family planning strategies but has historically been limited due to lack of investment over time, low funding to enable technology, and fragmentation of the field across disciplines. To make progress against the top line goal, concentrated, adaptable funding, new approaches and tools, and a cohesive hub-and-spoke organization with faculty and student pipelines are needed to enable the work. The Ovarian Contraceptive Discovery Initiative expands on current research at Northwestern University related to engineering in vitro tissue systems for modeling reproductive tissue to monitor key biological processes to improve the mechanistic understanding of follicle development and ovulation. This work supports the establishment of these tools within an integrated platform for the systematic study of ovarian biology with the express purpose of discovering, screening, and validating novel contraceptives. This platform will deliver a robust and optimized series of follicle and oocyte-targeted contraceptive targets, pathways, and screening tools. The Ovarian Contraceptive Discovery Initiative is a collaboration between four institutions and includes Dr. Francesca Duncan at Northwestern (Overall PI and Project 2 PI), Dr. Shuo Xiao at Rutgers (Project 1 PI), Dr. Amander Clark at UCLA (Project 3 PI), and Dr. Alex Shalek at the Ragon Institute (Project 4 PI) and is funded by the Bill & Melinda Gates Foundation.
Homeostatic to reactive hyaluronan matrices in ovarian reproductive aging
The female reproductive system ages decades prior to other organs and results in infertility, miscarriages, and birth defects - with such adverse consequences of particular concern as women worldwide are delaying childbearing. We recently identified fibrosis and inflammation as a hallmark of the aging ovarian microenvironment in which eggs grow and develop, and in this project we seek to investigate the underlying mechanism to ultimately counteract this phenomenon and improve reproductive longevity and outcomes. We will test the hypothesis that age-associated loss and fragmentation of a key extracellular matrix molecule (hyaluronan) in the mammalian ovary converts the microenvironment into a reactive matrix that drives fibrosis and inflammation. This is a joint project with Dr. Michele Pritchard and Dr. Mary Ellen Pavone (R01HD093726).
Extremely Long Lived Proteins and Female Reproductive Aging
Aging is associated with cellular and tissue deterioration and is a prime risk factor for chronic diseases and declining health, with the female reproductive system being the first to show overt manifestations of aging (i.e. decreased fertility, miscarriages, and birth defects). A key hallmark of aging in many tissues is loss of protein homeostasis or quality control mechanisms that protect the cellular proteome. In this project, we will open new avenues of discovery through the use of state-of-the-art mass spectrometry and imaging approaches to identify, visualize, and quantify a unique population of extremely long lived proteins in the oocyte and ovary that persist through the entire reproductive lifespan and likely fuel reproductive aging through accumulated damage. This is a collaboration with Dr. Jeffrey Savas (R21HD098498).
Targeting a critical aging pathway to promote prolonged ovarian and systemic health
The average age of menopause remains constant despite drastic increases in global life expectancy; consequently, women are living longer in the post-menopausal state with increases in cardiovascular disease, osteoporosis, depression, and sexual dysfunction. In parallel, the average age of a woman's first birth continues to rise, resulting in a shortened reproductive window and impaired fertility. A major aging pathway (mTOR) may be a key link between reproductive and total lifespan as mTOR activity increases with age in multiple organs, and mTOR inhibitors promote longevity in animals. This research will interrogate the impact of mTOR inhibitors on reproductive lifespan and offspring health in mice, as well investigate the relationship between advancing age and mTOR in human ovaries. Dr. Kara N. Goldman (PI) and Dr. Francesca E. Duncan (Co-I) are seeking to gain a clearer understanding of the role of this critical aging pathway in reproductive aging, thereby providing important therapeutic value that may lead to the development of useful clinical markers for aging and health. This work is funded through a Friends of Prentice grant through the Northwestern Memorial Foundation.
Hyaluronan, NRF2 and Protracted Female Fertility in Long-lived Naked Mole-Rats
In women, reduced fertility, increased risk of aneuploidy and miscarriage rise dramatically starting in the early thirties. Mechanisms that drive reproductive aging are poorly understood, and because women in the U.S. are delaying childbearing until older ages, there is an urgent need to develop innovative approaches and animal models to address this growing problem. In this project, we will develop the naked mole-rat, the longest-living rodent, which does not display reproductive aging, as a model to study factors that determine reproductive longevity. This project is a collaboration between Drs. Ned Place (PI), Francesca E. Duncan (Co-I), Vera Gorbunova (Co-I), and Melissa Homes (Co-I) (NSF Award: 2005919)
Sperm Safes: Maximizing the preservation and recovery of limited numbers of male germ cells
The goal of this work is to use a mouse model to test the efficacy and safety of using novel biological platforms to cryopreserve and recover small numbers of mammalian sperm to restore fertility. This work is funded by a Daniel Manela Research Grant through the Pediatric Oncofertility Research Foundation.
Radiation therapy-induced cellular senescence and extra-follicular ovarian environment
Radiation is one of the most effective therapies to eliminate unwanted cells, such as cancer cells, but it can simultaneously damage non-targeted tissues resulting in medically-induced complications. The ovary – and particularly the gametes within it - is highly radiosensitive, and thus, premature reproductive aging due to follicle loss is a potential unintended and devastating outcome of radiation treatment. Here we will investigate how radiation therapy affects the extra-follicular ovarian microenvironment, testing the novel hypothesis that radiation-driven cellular senescence in the stroma is a prime mechanism underlying compromised reproductive function. This work is a pilot project within the Center for Reproductive Health After Disease (P50 HD076188, Center Director: T.K. Woodruff).
Inflammatory Biomarkers of Female Reproductive Aging and Potential
In this project, we are validating whether a conserved inflammatory cytokine profile increases with age in human cumulus cells and whether it directly correlates with embryo outcomes in ART procedures. If successful, these studies will define a non-invasive reproductive aging signature that could provide a clinically relevant non-invasive readout of embryo potential. Such knowledge will thus have the dual benefit of improving reproductive health and offspring outcomes in women of advanced reproductive age. This work is a joint project with Dr. Mary Ellen Pavone and is funded through a Friends of Prentice grant through the Northwestern Memorial Foundation.
Chris Benz, MD (The Buck Institute)
Judith Campisi, PhD (The Buck Institute)
Amander Clark, PhD (University of California-Los Angeles)
Jennifer Gerton, PhD (Stowers Institute for Medical Research)
Kara N Goldman, MD (Northwestern University)
Jessica Hornick, PhD (Northwestern University)
Bruce Kimler, PhD (University of Kansas Medical Center)
T. Rajendra Kumar, PhD (University of Colorado Denver)
Mary Ellen Pavone, MD, MSCI (Northwestern University)
Ned Place, MD, PhD (Cornell University)
Michele Pritchard, PhD (University of Kansas Medical Center)
Jeffrey Savas, PhD (Northwestern University)
Birgit Schilling, PhD (The Buck Institute)
Melissa A Simon, MD (Northwestern University)
Alex Shalek, PhD (The Ragon Institute)
Chad Slawson, PhD (University of Kansas Medical Center)
Sadie Wignall, PhD (Northwestern University)
Teresa Woodruff, PhD (Northwestern University)
Shuo Xiao, PhD (Rutgers University)
For a list of publications from this lab, see: