Adult stem cells are required to maintain tissue homeostasis and decrease in stem cell function leads to the decline in health associated with aging. The causes of stem cell aging are poorly understood, and exploring basic mechanisms of stem cell regulation is vital to address this issue. The simple metazoan Hydra vulgaris is apparently "immortal", while other members of the genus undergo reproduction-induced senescence. The ability to compare the molecular mechanisms underlying the regulation of stem cells from two closely related animals with starkly different aging strategies is a unique and attractive feature of Hydra for aging studies;other well-established model organisms do not have seemingly "immortal" relatives. Furthermore, Hydra stem cells have attractive features for experimentation including: 1) Stem cell populations are well-characterized, 2) Due to recent advances in transgenic methods, the stem cells can be easily collected in large numbers and can be tracked and manipulated in vivo, and 3) Hydra stem cells share a gene expression profile with stem cells found in more complex animals. This includes the Piwi proteins, which are required for germline and stem cell function in animals. Our preliminary data suggest that Hydra Piwi proteins operate in a stem cell-specific pathway for maintaining tissue homeostasis and epithelial integrity in response to nutritional status. Because nutritional status is a conserved regulator of lifespan, we hypothesize that the Piwi pathway is a key player in the aging pathway of stem cells and we aim to understand how it functions in this context. Piwi proteins associate with a distinct class of small RNAs, piRNAs, and in Drosophila and mouse these Piwi/piRNA complexes modulate gene expression at the epigenetic and post-transcriptional levels. Hydra vulgaris stem cells have two strictly cytoplasmic Piwi proteins, allowing us to focus on identifyin post-transcriptional targets of the pathway. We are using a transgenic approaches to knockdown Piwi protein expression and test the function of the Piwi/piRNA pathway in each Hydra stem cell type. To identify targets of the pathway, we are: 1) Mapping piRNAs to a Hydra transcriptome to identify putative targets, 2) Testing for increased transcript levels of putative targets in piwi knockdown animals, and 3) Testing for a physical interaction between the putative transcript and Piwi/piRNA complexes. Finally, we are testing the hypothesis that the Piwi/piRNA pathway responds to nutritional status through the insulin pathway to regulate stem cell proliferation and tissue homeostasis.
We aim to understand both the upstream regulators of the pathway and the downstream targets. Ultimately, we hope to gain significant insights into the regulation of aging in stem cells that will translate to more complex organisms. My long-term goal is to establish Hydra as an important new model for dissecting the regulatory control of stem cell function and aging. Once I have established my own lab I will initiate collaborations in order to test the conservation of the Piwi/piRNA pathway in stem cell regulation in vertebrates.

Public Health Relevance

Stem cells are required to repair damaged tissue;as stem cells age they lose this ability thus causing the decline in health associated with aging. This proposal investigates the molecular mechanisms controlling the stem cells of Hydra, an animal with negligible aging. Understanding how Hydra stem cells retain longevity will give us a better understanding of why human stem cells age and shed light on possible therapies for extending stem cell longevity.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Scientist Development Award - Research & Training (K01)
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National Institute on Aging Initial Review Group (NIA)
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Murthy, Mahadev
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Yale University
Anatomy/Cell Biology
Schools of Medicine
New Haven
United States
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Juliano, Celina E; Reich, Adrian; Liu, Na et al. (2014) PIWI proteins and PIWI-interacting RNAs function in Hydra somatic stem cells. Proc Natl Acad Sci U S A 111:337-42