The incidence of a number of diseases - including cancer - increases with age. The aging process has a complex relationship with cell cycling: cell cycling maintains organ function by ensuring self-renewal, but this cycling is thought to drive mutation accumulation, and to eventually lead to senescence. Our long-term aim is to elucidate the strategies used by animals to minimize the negative impact of cell cycling, and to elucidate the compromises made between self-renewal and mutation accrual. We use the C. elegans germ line as a model system because four key features make it uniquely suitable to address these problems. First, it undergoes continuous cell turnover, with cell proliferation compensating for the loss of cells to gametogenesis;this makes it a suitable model systems for self-renewing organs, such as the intestine, that are an important cause of cancer. Second, its simple spatial organization - with cells laid out linearly according to a gradient of differentiation - makes it straightforward to quantitatively characterize fine differences between subpopulations of cycling germ cells. Third, powerful C. elegans genetics have identified a number of molecular controls of germ cells, and provide tools to finely manipulate these controls. Importantly, many of the controls of self-renewal and cell cycling - such as Notch, Cyclin E, and the Pumilio homologues fbf-1 and fbf-2 - have conserved functions in other animals, including humans. Fourth, the germ line undergoes senescence over a short period of ~1 week that makes aging experiments practical. Our research will pursue three related aims. First, we will identify molecular controls f cell cycling speed, building on previous work that has identified molecular components necessary for normal cell cycle progression. We will finely quantify expression of these components using computational tools we have developed, perturb their expression, and assay the effect on cell cycling speed. Second, we will assay the relationship between cell cycling and the onset of reproductive senescence. Third, we will ask what cell cycle control strategies are implemented by the C. elegans gonad to delay the onset of senescence;we will in particular focus on strategies that anticipate the future rate of cell turnover to optimize cell cycle parameters. We will address these strategies both from a theoretical angle, using computer simulations to elucidate their benefits, and from an experimental angle, using experiments crafted to uncover previously-unrecognized strategies employed by the gonad. Overall, our results will reveal how stem cell regulatory networks attain an important performance objective: fine control of cell cycle speed across subpopulations of cells to delay the onset of senescence.

Public Health Relevance

Links between cell cycling and senescence are known, but we are still missing a systems-level understanding of the objectives and constraints that underlie the tradeoffs made by biological systems. With the proposed research, we will gain insights into cell cycle control strategies used by animals - and in particular humans - to delay the onset of senescence and of diseases such as cancer.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM102635-03
Application #
8712512
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Lyster, Peter
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
City
Irvine
State
CA
Country
United States
Zip Code
92697
Cinquin, Amanda; Chiang, Michael; Paz, Adrian et al. (2016) Intermittent Stem Cell Cycling Balances Self-Renewal and Senescence of the C. elegans Germ Line. PLoS Genet 12:e1005985
Taylor, Pete H; Cinquin, Amanda; Cinquin, Olivier (2016) Quantification of in vivo progenitor mutation accrual with ultra-low error rate and minimal input DNA using SIP-HAVA-seq. Genome Res 26:1600-1611
Cinquin, Amanda; Zheng, Likun; Taylor, Pete H et al. (2015) Semi-permeable Diffusion Barriers Enhance Patterning Robustness in the C. elegans Germline. Dev Cell 35:405-17
Chiang, Michael; Hallman, Sam; Cinquin, Amanda et al. (2015) Analysis of in vivo single cell behavior by high throughput, human-in-the-loop segmentation of three-dimensional images. BMC Bioinformatics 16:397
Meeds, Edward; Chiang, Michael; Lee, Mary et al. (2015) POPE: post optimization posterior evaluation of likelihood free models. BMC Bioinformatics 16:264
Reyes de Mochel, Nabora Soledad; Luong, Mui; Chiang, Michael et al. (2015) BMP signaling is required for cell cleavage in preimplantation-mouse embryos. Dev Biol 397:45-55
Chiang, Michael; Cinquin, Amanda; Paz, Adrian et al. (2015) Control of Caenorhabditis elegans germ-line stem-cell cycling speed meets requirements of design to minimize mutation accumulation. BMC Biol 13:51
Wong, Brandon G; Paz, Adrian; Corrado, Michael A et al. (2013) Live imaging reveals active infiltration of mitotic zone by its stem cell niche. Integr Biol (Camb) 5:976-82