Supervised by: Dr. Yousin Suh, Department of Genetics and Development, Columbia University Irving Medical Center
Project Background
My proposed research project delves into ovarian aging, an area of study critical to discovering more about women’s health. Studying ovarian functional decline does more than allow researchers to identify intervention strategies to extend fertility health-span; it also serves as a uniquely valuable model for understanding aging as a whole. As one of the earliest organs to exhibit functional decline, the ovary provides key insights into systemic aging. Studying age-related diseases in mice typically requires waiting over 24 months for natural aging. In contrast, ovarian aging becomes evident in just nine months, making it a more time- and cost-efficient model for aging research. When considering ovarian aging, people tend to fixate on infertility and reproductive health. While fertility is an important area of study, the consequences of ovarian aging extend well beyond reproduction, contributing to the progression of postmenopausal conditions like osteoporosis and cardiovascular disease. Despite women comprising roughly half of the global population, women’s health has historically been under-researched and underfunded, particularly regarding the biological mechanisms that drive ovarian aging. Genome studies have shown that age at natural menopause (ANM), a proxy for reproductive aging, is highly heritable. Through genome wide association studies, hundreds of variants associated with ANM have been linked to DNA damage response and repair pathways, suggesting that gene deficiencies may delay ovarian aging.
Objectives
I intend to research the DNA Helicase B (HELB) gene in particular, whose reduced gene expression is tied with delayed ANM. The overarching hypothesis of this project is that HELB deficiency delays ovarian aging by enhancing meiotic recombination, a key determinant of both gamete (reproductive cell) quality and quantity. This project will include writing a literature review about HELB and more broadly, genome maintenance or DNA integrity, of which we think HELB participates in. I will also be writing grants to determine the effect of HELB deficiency on meiotic recombination and oocyte competence, evaluate the role of HELB deficiency on DNA end resection activity and meiotic crossover formation, and assess whether HELB deficiency mitigates the age-related increase in chromosome segregation errors in oocytes.
Methodology
During this summer, I will execute a two-pronged approach: a deep-dive literature review and a rigorous technical training phase. First, I will identify the specific proteomic interactors of HELB to synthesize a review that examines genome maintenance and DNA integrity. I aim to produce a review suitable for peer-reviewed publication. Simultaneously, I will shadow lab mentors to master high-level laboratory techniques, including immunofluorescence staining, advanced microscopy, and chromosome spreads. Although I have practiced these at a rudimentary level, I aim to achieve the technical precision required for professional reproductive research. These techniques will allow me to localize HELB within tissue samples via knockout mouse models, where the gene has been selectively inactivated. Through this six-week immersion, I will not only develop the technical acumen for my future career but will also contribute to our understanding of how microscopic cellular processes dictate the trajectory of human life.