The ability to regenerate tissues declines in aging individuals. This decline is a manifestation of stem cell dysfunction, resulting from damage to stem cells themselves, as well as from changes in the organism that impair its ability to host healthy stem cell populations. To ensure success in regenerative therapies, it is critical to understand the mechanisms leading to such dysfunction.
Characterizing these mechanisms is difficult in humans, as it requires detailed genetic analysis of stem cell function within aging individuals. Studying age-related dysfunction in model organisms is thus an important strategy to explore basic rules and concepts illuminating regenerative decline. The fruitfly Drosophila melanogaster represents such a model, with a rich history of contributions to biomedical research. Studies in fruitflies rely on a plethora of genetic tricks that allow identifying determinants of many biological processes. Importantly, these organisms age in a manner of weeks, not years, and the effects of genetic perturbations on healthspan and lifespan can thus be analyzed efficiently.
The applicant has established the fruitfly as a model to study the age-related decline in regenerative capacity. This work has identified several evolutionarily conserved regulatory mechanisms that impair stem cell function in aging organisms, and has demonstrated intervention strategies that result in improved maintenance of regenerative capacity, tissue function, and in lifespan extension.
The applicant now plans to translate this work into vertebrate and human stem cell systems as a means to develop strategies to extend human healthspan. Initial studies will focus on the mouse respiratory system, which regenerates from a stem cell population that closely resembles fly intestinal stem cells. The applicant will use the conceptual and mechanistic insights generated in the fly to develop testable hypotheses about efficient interventions that might regulate the regenerative efficiency of these stem cell populations. This work will then be expanded to characterize similar mechanisms in human embryonic and induced pluripotent stem cells.
Specifically, this application aims to test the effects of two regulatory principles that allow stem cell activity to be controlled by nutritional conditions and by environmental stress. The applicant has identified a role for these regulatory mechanisms in the control of activity and maintenance of stem cells in aging flies, and proposes to use this insight in a targeted approach to characterize stem cell regulation in vertebrates. Due to its conceptual nature, this work will have implications for the planning and design of regenerative strategies in humans. The applicant thus aims to significantly narrow the divide between basic and applied research, with a direct focus on regenerative medicine.
Statement of Benefit to California:
Aging is a decisive risk factor for degenerative diseases and cancer, pathologies that represent the two extremes of stem cell dysfunction. Moreover, the success of stem cell therapies is likely influenced by the age of the host, as stem cell function in aging individuals is negatively impacted by changes in the systemic environment.
Identifying mechanisms of stem cell aging is thus critical to improve therapeutic strategies relying on regenerative approaches.
At the same time, age-related stem cell dysfunction is inherently difficult to study, as it is multifactorial, requires new conceptual approaches, and poses a challenge to established research protocols. In this context, combining the speed and efficiency of genetic model organism research with clinically relevant studies of regeneration and stem cell function in vertebrate systems is expected to be an extremely powerful approach. New concepts informing therapeutic strategies to improve stem cell function and extend human healthspan are expected to emerge from such work.
The applicant’s proposed research program will bring this unique combination to California, fostering new avenues of stem cell research within the state and promising to further advance the excellence of the California stem cell research community. It is anticipated that the applicant’s research program will integrate seamlessly into the existing research infrastructure and community at the host institution and within the stem cell research community in California, creating synergies that will lead to breakthrough discoveries in regenerative medicine.
The people of California will thus benefit both by strengthening the position of the state as a center for scientific excellence, as well as by fostering research that is at the forefront of our pursuit to optimize regenerative therapies to combat chronic and age-related diseases.