The following description was taken from the R01 version of this FOA.
The human apolipoprotein E (ApoE) gene has been found to have a strong association with exceptional longevity. The ApoE protein is a component of several lipoproteins and plays a key role in lipid metabolism, including the redistribution of lipoproteins and cholesterol. ApoE has also been shown to be involved in important cellular functions such as oxidative processes, inflammation, macrophage, glial cell and neuronal cell homeostasis, adrenal function, central nervous system physiology. Common isoforms of the ApoE protein include E4, E3 and E2 which are encoded by the e4, e3 and e2 alleles, respectively. In particular, the e2 allelic variant has been found to be more prevalent among centenarians and associated with decreased susceptibility to cardiovascular disease and Alzheimer’s disease. A recent survey of publications on genes associated with human longevity noted that the presence of the e2 allele was generally associated with longevity across different ethnic groups. In Caucasian populations, survival to advanced ages has been shown to be more likely for carriers of the e2 allele than for e3 homozygotes and less likely for the carriers of the e4 allele.
Carriers of the different ApoE alleles also show differences in the incidence of coronary artery disease (CAD), peripheral atherosclerosis, Alzheimer’s disease and other age-related diseases. Epidemiologic studies have also observed that individuals with the ApoE2 genotype maintain lower serum total cholesterol levels, higher HDL levels, and lower total cholesterol: HDL ratio from midlife through late life compared to ApoE3 and ApoE4 subjects after controlling for the effects of age, gender, use of cholesterol-lowering medications, systolic and diastolic blood pressure, blood sugar, diet restriction, and BMI. The e2 allele has also been reported to have a variety of neuroprotective effects that may contribute to its association with decreased risk for Alzheimer’s disease. However, ApoE2 has also been found to be associated with increased likelihood of renal disease, age-related macular degeneration (AMD) and hypertriglyceridemia, thus demonstrating a mixture of protective and adverse effects (but predominance of protective effects). This combination of protective and adverse effects will be an important consideration for the research aimed at translating knowledge on effects of the ApoE2 variant into potential therapeutic targets for enhancing health span.
Furthermore, the mechanisms underlying the e2 relationship with longevity or health span remain relatively unknown. Structural differences in the ApoE isoforms determine functional variations that affect cardiovascular, neurological and immune functions of cells. Isoforms of ApoE differ in structure from each other only at amino acids 112 and 158. ApoE2 has cysteine at both sites, E4 has arginine at both positions and E3 contains cysteine at 112 and arginine at 158. Such minor differences give rise to variability in domain interactions with multiple molecules including low density lipoprotein receptors (LDLRs), cell-surface heparin sulfate proteoglycans (HSPGs), ATP binding cassette protein 1 (ABCA1), and low-density lipoprotein-related proteins (LRPs), as well as with protein stability and protein folding. These characteristics in turn influence the activity of ApoE in an allele-specific manner in both healthy and pathological states. The ApoE alleles may also contribute to epigenetic alterations of the ApoE CpG islands, possibly involving protein binding, chromatin remodeling, and specific RNA regulation in an age-dependent manner. Thus, interplay between genetic and epigenetic variations could also be one of the molecular mechanisms behind ApoE’s association with multiple physiological conditions and diseases.
Despite the evidence for a strong association of ApoE2 with health span and longevity, fundamental hurdles to the translation of ApoE2 into novel therapeutics include the lack of information on genotype-phenotype relationships (e.g., risk for age-related conditions, disease-free survival) and the poor understanding of the functional pathways involved in mediating the protective effects. Of particular importance is the question of whether the beneficial effects of ApoE are primarily due to enhanced expression/activity of ApoE in general or whether there are e2-specific allelic effects. A greater understanding of this issue would help to determine additional types of translational studies which may be needed such as: (1) the mechanisms by which e2 carriers seem to age more successfully than e3 and e4 carriers; (2) potential interactions of e2 with other ApoE alleles involved in the functional effects; (3) allele-specific effects on a variety of cellular functions; and (4) epigenetic modifications of ApoE as a function of age and cell type. Further studies addressing these questions would facilitate the elucidation of mechanisms underlying the effects (beneficial and adverse) of e2 and open up new avenues of target discovery for promoting healthy aging.
The focus of this FOA is on studies of ApoE leading to a better understanding of the factors and functional pathways that mediate the effect of e2 in comparison to other ApoE isoforms in longevity, and risks for aging-related conditions. Studies that examine effects on pathways influencing risk for multiple age-related conditions (e.g. both cardiovascular disease and Alzheimer’s disease) are of particular interest, including identifying shared pathways of proposed aging mechanisms. Studies comparing relationships of ApoE isoforms to these factors in individuals of differing ages are also of interest, particularly in regard to the influence of aging mechanisms and/or age-related morbidities.
Examples of potential research strategies to address the above research objectives include but are not limited to:
- Secondary/meta data analyses of human phenotypic data from epidemiologic studies, clinical trials, or other clinical studies, based on existing databases or de novo data collection (from ongoing clinical research studies), to gain better understanding of clinical relationships of ApoE2 and other ApoE variants to risk and progression of clinical outcomes, and to identify potential physiologic factors that mediate such relationships. This also includes gaining a better understanding of the pharmacogenetics effect of ApoE isoforms on various pharmacological and non-pharmacological interventions for age-related diseases including brain aging and AD. Attention to both potential adverse and beneficial effects of ApoE2 is encouraged.
- Molecular profiling (genomic, proteomic, lipidomic and metabolomic) of stored human biospecimens or specimens collected de novo (e.g., additional follow-up visit of participants in an existing cohort) to understand relationships of ApoE genotypes, mRNA and protein levels, cellular functional pathways and pharmacogenetics effects that may be affected differentially by ApoE variants, and the relationships of these factors and risk for age-related diseases. Consideration of multi-dimensional integrative omics analysis is encouraged.
- Examination of the epigenetic regulation of different ApoE alleles, and post-translational modification of different ApoE isoforms, on development and progression of age-related diseases (e.g., epigenetic signatures of ApoE and enhancer/suppressor activity of epigenetic modifications on ApoE expression).
- Studies using animal models, human or animal in vitro cultured cells including iPSCs and gene-edited cells, and in vivo humanized ApoE animal models, to elucidate the molecular, biochemical, cellular, and physiological mechanisms and understand cellular and functional differences related to ApoE allelic differences, and their potential effects on risk for multiple in vivo aging-related pathologies.
- In vitro or lab animal studies on effects of small molecules that might act as structural modifiers, modulate ApoE effects, influence epigenetic or other regulation of ApoE expression or functions, or influence pathways differentially affected by ApoE variants, to mimic protective effects of ApoE2.
For proposed studies using data from established cohorts, applicants are responsible for adhering to the individual study policies governing ancillary projects and access to clinical trials data and/or biorepository samples.
Deadlines: standard dates apply
R01 – http://grants.nih.gov/grants/guide/pa-files/PAR-16-370.html
R21 – http://grants.nih.gov/grants/guide/pa-files/PAR-16-371.html
Filed Under: Funding Opportunities