Posted Date: September 19, 2017
Letter of Intent Due Date: December 31, 2017
Application Due Date: January 31, 2018
This FOA issued by the National Institute of Dental and Craniofacial Research solicits exploratory/developmental Research Grant (R21) applications from institutions/organizations that will elucidate the molecular mechanisms of aging in dental, oral and craniofacial tissues.
Temporal physiological changes in tissues, organs and organ systems are considered a part of normal aging. However, these changes result in an age-associated reduction of tissue resiliency and functional capacity, and contribute to increased incidence of disease. Transition from healthy aging to disease follows a continuum of changes that are modulated by intrinsic and extrinsic factors. Mechanistic studies of inflammation, tissue healing and regeneration, and epigenetic gene regulation revealed interconnected relationships among these processes and led to the development of a new idea that aging is an adaptive and plastic process that could be manipulated for improving healthspan, rather than just extending lifespan. This FOA emphasizes the functional significance of regulation of age-related changes in the areas of immunity, tissue regeneration and epigenetics.
- Alterations that affect the aged innate and adaptive immune system contribute to increased disease susceptibility of the elderly. These alterations drive subclinical inflammation, or inflammaging, and are thought to be responsible for development and progression of age-related diseases such as autoimmune diseases, osteoporosis and neurodegenerative disorders. Mechanisms responsible for producing the increasingly compromised inflammatory status remain unclear. For example, it is unknown whether inflammasomes are activated in human aging and whether they contribute to the onset of age-associated disease. Changes in adaptive immune system are characterized by a decrease in naive T- and B-cells, an increase in memory cells and a progressive reduction in the T-cell and B-cell receptor repertoire. Innate immune system alteration with age, including developmental shift toward the myeloid lineage of hematopoietic stem cells (HSCs), age-related dysfunction of neutrophils, natural killer cells, monocytes, macrophages and dendritic cells has been reported. Changes in the tissue microenvironment, such as accumulation of cell debris, and systemic changes in metabolic and hormonal signals, also likely contribute to development of chronic inflammation.
- Changes leading to collapse of clonal diversity of stem cells, and decreases in age-associated self-renewal and differentiation capacity highlight the need for better understanding of the mechanisms of stem cell regulation and clonal dominance. In this regard, it is noteworthy that amelioration of age-associated changes and improved normal tissue homeostasis have been achieved in aged mice by transient expression of stem cell reprogramming factors. Also, it has been suggested that aging of HSCs at least in part results from chronic activation of inflammatory signaling. Further, it is thought that in addition to altered intrinsic stem cell dysfunction, stem cell niche components, such as growth factors, somatic cells, immune cells, extracellular matrixes (ECM), innervating neuronal fibers, and vasculature, may be affected by aging, and harnessing these different elements could be instrumental for developing new strategies to improve stem cell functions and optimize tissue healing and regeneration. In light of these new findings, it would be important to conduct studies that examine consequences of the ablation of senescent cells and, elucidate how modulation of inflammatory signaling and immune cell phenotypes, and manipulation of intracellular and intercellular signaling pathways among these cells are controlled during the process of aging.
- Epigenetic remodeling in response to environmental stimuli and epigenetic drift reduce genomic stability, drive aging process and affect longevity. These changes include reduced bulk levels of the core histones, altered patterns of histone post-translational modifications and DNA methylation, replacement of canonical histones with histone variants, and altered noncoding RNA expression. These changes result in altered local accessibility to genetic materials, leading to aberrant gene expression, reactivation of transposable elements, and genomic instability. Understanding regulation and functional significance of these epigenetic changes with regard to the inheritance of aging characteristics, lifespan modulation by chromatin modulators and characterization of epigenetic marks across lifespan are knowledge gaps that remain to be addressed.
Overall, this FOA aims to stimulate hypothesis-driven research to understand mechanisms of healthy aging and disease in DOC tissues with a focus on inflammation, tissue healing and regeneration, and epigenetics.