DP1AG077430

Cracking the Code of Transgenerational Inheritance of Behavior - Project Summary

Transgenerational epigenetic inheritance (TEI) has been observed in worms, flies, and mice, and proposed in humans (e.g., Dutch Hunger Winter), but the underlying and regulatory molecular mechanisms are largely unknown. Similarly, we do not yet understand how ubiquitous trans-kingdom signaling between pathogens and hosts is. Therefore, it is critical to study these mechanisms in model systems.

We recently discovered that the nematode C. elegans, which both eats and is infected by bacteria, can survey its environment, detect and learn to avoid pathogens, and then pass this information on to four generations of its progeny (Moore, et al., Cell 2019). We propose that this is a nascent form of adaptive immunity. Well-conserved molecular processes (RNA interference, COMPASS histone modification, piRNAs) across several tissues (intestine, germline, and neurons) are required to alter behavior in response to Pseudomonas aeruginosa (PA14). Worms "read" small RNA bacterial signals, interpret this information as a predictor of future infection, and transmit the information to alter behavior by downregulating a neuronal gene with complementary sequence (Kaletsky, et al. bioRxiv 2020; Kaletsky et al. Nature, in press).

How is the sRNA signal conveyed from the germline to neurons? We found that the TY3/Gypsy retrotransposon CER1 is required for learned pathogenic avoidance, TEI, and survival on PA14. This is paradigm shifting: conventional wisdom holds that retrotransposons are deleterious, and that piRNAs are critical to repress these genomic parasites. Our results instead suggest that CER1 may have been selected to fight against the most abundant pathogens in C. elegans' environment. We hypothesize that CER1 forms vesicle-like particles that carry sRNAs to neurons.

Proposed experiments will characterize the nature of the germline-to-neuron signal, determine the evolutionary conservation of the mechanism, and determine how the transgenerational "clock" is set. Because the molecular components we have already observed are conserved, our results will identify candidate molecular requirements for TEI in other animals.

The Trustees Of Princeton University

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.310 - Trans-NIH Research Support

National Institute on Aging (NIA) [HHS - NIH]

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Princeton, New Jersey 085406000 United States

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NIH Directors Pioneer Award Program (DP1 Clinical Trial Optional) (RFA-RM-20-011)

Amendment Since initial award the total obligations have increased 498% from $1,116,759 to $6,678,219.