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Current Rotation/PhD Thesis Projects

How Does Aging-Associated Loss of the Y Chromosome Contribute to Heart Disease?

Why do men become increasingly susceptible to heart disease as they age? One intriguing possibility is the progressive loss of the Y chromosome from individual cells, a phenomenon known as mosaic loss of the Y chromosome (mLOY). Although Y-chromosome loss is common in aging men and has been linked to cardiovascular disease, we know remarkably little about which cells lose their Y chromosome, when this occurs, or how these cells contribute to heart damage. Our laboratory is developing a unique mouse model with an inducible, Y-chromosome-linked fluorescent reporter that will allow us to investigate these questions in unprecedented detail. In this rotation/PhD thesis project, students will use this innovative genetic system to determine how Y-chromosome loss changes with age, identify the cardiac and immune cell populations affected, and investigate whether cardiac injury caused by myocardial infarction (heart attack) or pressure overload accelerates the accumulation of Y-deficient cells. By combining mouse genetics, cardiac physiology, advanced imaging, and single-cell genomics, students will explore whether Y-chromosome loss alters immune-cell behavior, promotes cardiac fibrosis, and impairs recovery following injury. The ultimate goal is to uncover a previously underappreciated connection between aging, sex chromosomes, and heart disease—and identify new mechanisms that could explain why cardiovascular disease becomes increasingly common and severe in older men.

Building the Female Heart: How X-Chromosome Mosaicism Shapes Cardiac Development and Aging

Every female mammal is a genetic mosaic: some cells express their maternal X chromosome, while others express their paternal X chromosome. Yet we know surprisingly little about how these two populations contribute to the development, organization, and lifelong function of the female heart. Does the pattern of X-chromosome inactivation established during embryonic development persist throughout life, or does aging selectively favor cells expressing one parental X chromosome over the other? Our laboratory is developing a unique mouse model with inducible fluorescent reporters integrated directly into the maternal and paternal X chromosomes, allowing us to distinguish and track these two populations in the developing and adult heart. In this rotation/PhD thesis project, students will investigate how maternal-X-active and paternal-X-active cells contribute to different cardiac tissues, whether their spatial organization changes during development and aging, and whether the two populations exhibit distinct molecular or functional properties. By combining innovative mouse genetics, developmental biology, advanced imaging, and single-cell genomics, students will explore how X-chromosome inactivation shapes the architecture of the female heart. The ultimate goal is to uncover a fundamental and largely unexplored aspect of female cardiac biology: whether the organization and maintenance of X-chromosome mosaicism contribute to lifelong heart health and help explain sex differences in cardiovascular aging.

The Protective Mosaic: Can Healthy Cells Protect the Female Heart from X-Linked Genetic Disease?

Why can two women carrying the same X-linked genetic mutation experience dramatically different disease outcomes, and why are females often less severely affected than males carrying the same mutation? One intriguing explanation lies in X-chromosome mosaicism: in females, some cells preferentially express the normal X chromosome, while neighboring cells express the chromosome carrying the mutation. Could this mixture of genetically distinct cells protect the female heart from inherited disease? Our laboratory is developing an innovative mouse model with inducible fluorescent reporters integrated directly into the maternal and paternal X chromosomes, allowing us to distinguish and follow cells according to which parental X chromosome is active. In this rotation/PhD thesis project, students will introduce a cardiac disease-associated mutation into one X chromosome and investigate how mutant-active and normal-active cells contribute to heart development, function, and responses to injury. Using mouse genetics, cardiac physiology, advanced imaging, and single-cell genomics, students will determine whether normal cells compensate for neighboring mutant cells, whether disease or aging changes the relative abundance of these populations, and whether cardiac stress disrupts this potentially protective mosaicism. The project will also examine how X-linked genes that escape X-chromosome inactivation influence these responses. The ultimate goal is to discover whether X-chromosome mosaicism provides a natural mechanism of protection against inherited heart disease, offering new insights into why the same genetic mutation can produce profoundly different clinical outcomes in males and females.

Postdoctoral Positions

Fully funded postdoctoral positions are presently available in the Conlon Lab whose studies focus on identifying the molecular networks that are essential for early heart development and how alterations in these networks lead to congenital heart disease. For these studies, we use a highly integrated approach that incorporates developmental, genetic, proteomic, biochemical and molecular based studies in mouse and stem cells.

Candidates should have recently obtained or be about to obtain a Ph.D. or M.D. in a field of biological science and should have a strong publication record. Outstanding and highly motivated candidates should apply by email to Dr. Frank L. Conlon and include a CV/resume, three references and description of your specific interest in our research programs.