This application for a K08 award describes a multidisciplinary 5-year training program to facilitate Dr. Laren Becker's career development as an independent academic physician-scientist. The candidate is a MD, PhD who joined the Gastroenterology Department at Stanford in 2009 and now seeks to build on his research experience to attain his long-term career goal of becoming an independent investigator, directing a research program in neurogastroenterology and aging. This K08 award will provide Dr. Becker with the support and protected time necessary to accomplish the following training objectives: (1) to become an expert in neurogastroenterology, immunology and aging, (2) to become proficient in immunology research including mastering techniques such as immunophenotyping and creation of bone marrow chimeras, (3) to acquire skills important for an academic career including scientific writing and oral presentation, and (4) to submit an R01 application during year 4. To achieve these goals, the candidate has assembled a strong mentoring team of experts in GI immunology, aging and neurogastroenterology-all of whom have successfully mentored young scientists. Dr. Becker's career development plan includes regular meetings with his mentors and advisory committee, didactics, and attendance at local and international meetings. Stanford, a world-class institution with particular strength in immunology, stem cell and aging research, is the ideal environment for developing the candidate's academic career. Research Aging causes physiologic changes in gastrointestinal intestinal function that contribute to many age-related disorders. The etiology of these disorders is likely multifactorial, but loss and degeneration of neurons in the enteric nervous system (ENS) likely plays a role. The proposed studies are predicated on the finding that age- associated cognitive decline is likely due to loss of neural stem cells related to central nervous system inflammation. While unknown whether a decline in enteric neural stem cells (ENSCs) contributes to loss of enteric neurons with aging, the discovery that ENSCs are involved in neurogenesis supports this interpretation. Interestingly, Foxo3, a transcription factors linked to longevity in humans was recently found to play a role in inflammatory disorders including Crohn's disease and Rheumatoid arthritis. Loss of Foxo3 signaling in dendritic cells (DCs) was found to increase IL-6 production and drive inflammation. Based on preliminary data which found both a decline in Foxo3 expression and rise in proinflammatory cytokines in the ENS microenvironment with aging, it is posited that aging increases inflammation due to reduction in Foxo3 signaling in DCs which in turn causes age-related ENS disturbances via a decline in functional ENSCs. This hypothesis will be addressed in two ways. First, the role of Foxo3 in age-dependent loss of ENSCs will be examined. Specifically, the candidate will assess whether 1) Foxo3 expression in DCs declines with aging, 2) Foxo3 deficiency leads to premature loss of ENSCs and enteric neurons, and 3) Foxo3 deficiency in immune cells in particular is responsible for loss in the ENS. Second, how age-dependent Foxo3 modulation of inflammation impacts ENSCs will be examined. Specifically, the candidate will evaluate whether 1) aging causes increased proinflammatory cytokines and immune cells in the ENS microenvironment and Foxo3 deficiency augments these inflammatory changes, 2) blocking the proinflammatory cytokine IL-6 will improve survival of ENSCs in culture, and 3) administration of IL-6 in vivo will inhibit neurogenesis. Successful completion of the proposed sudies will offer valuable new insights regarding the mechanism of age- related changes of the ENS. Additionally, it will provide proof of principle that immunomodulatory therapies have a role in age-associated gastrointestinal disorders. This proposal will serve as a platform for Dr. Becker to acquire additional training in GI immunology and aging, crucial to developing a research niche in neurogastroenterology. Additionally, this research will provide the foundation for future studies as an independent investigator including evaluating whether targeting inflammation via blockade of IL-6 in vivo can reverse age-related changes to the ENS, whether aging-induced inflammation plays a similar role in humans, and ultimately whether immunomodulatory therapies may serve as therapy for aging associated GI disorders.
Gastrointestinal disorders such as constipation and fecal incontinence are common in the elderly population and adversely affect quality of life and place a heavy financial burden on society. Disturbances in the neural network that controls the gut, known as the enteric nervous system, are seen with aging and likely play a significant role in these disorders. The cause of these disturbances is not clear but the research that we propose will likely improve our understanding of the aging process and potentially lead to new therapies that can reverse or prevent the decline in gut function.
| Becker, Laren; Nguyen, Linh; Gill, Jaspreet et al. (2018) Age-dependent shift in macrophage polarisation causes inflammation-mediated degeneration of enteric nervous system. Gut 67:827-836 |
