1999 — 2002 |
Williams, Christina L |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Mechanisms Underlying Choline Enhancement of Memory @ Boston University Medical Campus
Research from our laboratories has demonstrated that choline supplementation during perinatal development produces long-term facilitation of spatial memory, attention, and temporal processing, and inoculates against age-related memory decline, while deficiency of choline produces some deleterious effects. These long-lasting behavioral changes are accompanied by a complex pattern of changes in the neuroanatomy, neurochemistry, and neurophysiology of the septohippocampal system. The findings from several of the laboratories during the past funding period provide the foundation of the Aims of this Project. We have discovered that supplementation with folate, like choline , during the second half of pregnancy improve memory performance of the offspring. This finding is particularly important because the metabolism of choline and methyl-folate are closely interrelated. We propose to carefully characterize the nature of folate effects on memory and compare these effects to choline in order to determine if there might be a common mechanism underlying the effects of both these nutrients on memory function. As well, despite recommendations to supplement folate to women periconceptually to prevent neural tube defects, little is known about the long-term effects of folate during the latter half of pregnancy on brain or behavior. We aim to characterize the behavioral, neuroanatomical, and neurochemical effects of prenatal folate supplementation and deficiency. We have also determined that during choline supplementation to the dam's diet, the majority of choline ingested by the dam is converted to phospatidylcholine (PtdCho) and then delivered to the fetus. In addition, we have observed that a lipoprotein containing apolipoprotein E (apoE) can effectively deliver PtdCho to cells in vitro. We suggest that an apoE lipoprotein is responsible for delivery of PtdCho to brain cells in vivo. In addition, we have determined that apoE deficient mice have a selective deficit in working memory that can be detected in mice as young at 4-5 months of age. We hypothesize that apoE deficient mice may actually be suffering from choline insufficiency through life because they cannot effectively deliver PtdCho to brain cells. Thus, the second aim of our Project is to examine the behavioral neuroanatomical and biochemical consequences of prenatal or lifelong choline supplementation to apoE deficient mice in order to determine whether we can rescue them from these lifelong behavioral deficits.
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0.928 |
2005 — 2009 |
Williams, Christina L |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Choline, Merthyl Metabolism, Cognition: Mechanisms and M @ Boston University Medical Campus
behavioral /social science research tag; laboratory mouse; mother /embryo /fetus nutrition
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0.928 |
2017 — 2019 |
Badea, Alexandra (co-PI) [⬀] Colton, Carol Anne [⬀] Gottschalk, William Kirby Lutz, Michael William Thompson, Joseph Wilbur (co-PI) [⬀] Williams, Christina L |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Sex and Apoe Genotype Interact to Alter Immune Regulated Metabolism in Ad
The timing of onset and the severity of the disease process in Alzheimer?s disease (AD) are varied and involve risk factors that include the expression of gene alleles of APOE4. Biological female sex is also implicated as a strong risk factor for AD. However, despite accumulating evidence supporting this association, recent large population-based analyses indicate that this association is complex. Immunity, like sex and APOE genotype, is a primary disease factor in AD and impacts both the onset and pathological features of neurodegenerative events. The impact of sex hormones on immunity suggests that this additional interaction may contribute to the role APOE4 plays in AD. How sex, APOE genotype and immunity interact to initiate or amplify AD pathology, however, remains essentially unknown. Our preliminary data point to a shift in metabolic pathways that is directly controlled by immunity, is impacted by sex and by APOE genotype and which may serve as an underlying and unifying mechanism defining the disease process. In this proposal we will identify these metabolic pathways and test if changing estrogen levels as found in menopause alters these metabolic outcomes to worsen disease and in an APOE genotype dependent manner. To accomplish these goals we have developed a series of mouse models that permit direct analysis and comparisons of changes in brain metabolism under conditions where APOE genotype and female sex interact in a more-human like immune background. To fully characterize these models, we will use advanced phenotyping techniques that include unbiased proteomics, transcriptomics and metabolomics The use of laser capture microdissection combined with genomic or proteomic analysis will permit regional and/or cellular localization of changed pathways. Measuring pathway flux with heavy labeled isotopes allows us to directly confirm specific pathway differences based on biological sex, genotype or age. Initiating estrogen depletion in our mouse models using ovarian chemical disruption allows us to determine and compare the effect of lack of estrogen (menopause) on the pathological phenotypes. Overall, our research plan will allow us to identify critical pathways and to widen our knowledge of the impact of AD-like pathology on multiple brain functions, including immunity. Importantly, using bioinformatics tools we will be able to compare across the experimental data sets generated from our analyses of the mice models, to human tissue metabolites and finally to corresponding available human data sets outside of Duke, enabling us to confirm and extend our results.
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0.958 |
2018 |
Colton, Carol Anne (co-PI) [⬀] Finch, Elizabeth A [⬀] Williams, Christina L |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Better Than Drugs: Neuroprotection by Exercise in a Mouse Model of Menopause in Alzheimer's Disease
Biological sex (genetic and hormonal), and lifestyle are major risk factors for cognitive decline during normal aging and the onset and progression of Alzheimer?s disease (AD). Thus, being female and physically inactive increases the susceptibility for age-related cognitive impairments and AD, particularly following menopause. Physical exercise has emerged as a powerful strategy for maintaining brain health and resilience during aging and for staving off the cognitive decline associated with neurodegenerative disease. However, despite strong evidence for sex differences, hormonal effects, and lifestyle factors in cognitive aging and disease, studies to unravel the how interactions among these factors affect female vulnerability and the mechanisms that mediate these effects are lacking. Here we propose to address these fundamental issues that are of significant consequence for the cognitive health and well-being of more than half of the human population: the potential neuroprotective and cognitive benefits of physical exercise on the female brain, with a specific focus on the greater susceptibility of post-menopausal females to age-related cognitive decline and AD. To address these questions, we will combine two powerful mouse models: 1) our CVN-AD mouse model of AD, which exhibits neuropathological features similar to those of humans with AD as well as exacerbated AD-like neuropathogenesis and resistance to therapeutic intervention in females; and 2) a mouse model of menopause, in which a chemically-induced progressive loss of ovarian hormones mimics the human menopausal transition. Our focus on building an AD mouse model for investigating female physiology has the potential to enhance health-related research on female aging and AD. We will first determine the effects of transitional menopause on memory, neuropathogenesis, and gene expression in CVN-AD and control mice. We will then investigate the extent to which exercise training at different stages of AD-like disease and the menopausal transition can attenuate the decline in cognition and brain function in menopausal and hormonally- intact CVN-AD females and the molecular pathways shared by these processes. Together, these studies will serve as an exploratory first step to answer fundamental questions relevant to healthy brain aging and neurodegenerative disease in females and may lead to the discovery of novel mechanisms that mediate these processes and the development of more effective intervention strategies to sustain and protect the cognitive health and well-being of aging females with and without AD.
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0.958 |