1988 — 1989 |
Geula, Changiz |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Cortical Cholinergic Fibers in Aging and Alzheimers's Ag @ Beth Israel Deaconess Medical Center |
0.906 |
1992 — 1993 |
Geula, Changiz |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Cholinergic System in Alzheimer's Disease @ Beth Israel Deaconess Medical Center
Although degeneration of cortical cholinergic innervation is a consistent feature of Alzheimer's disease (AD), many questions concerning the nature and origin of this degeneration remain unanswered. Of note, no comprehensive histochemical survey exists of the cholinergic system in AD. The major goal of the research outlined in this proposal is to provide a comprehensive survey of the cholinergic system in AD using histochemical and morphological methods. The existence of regional variations in the loss of cortical cholinergic fibers in AD will be determined using a histochemical method for acetylcholinesterase (AChE). the loss in number and size of the cholinergic neurons of the basal forebrain and brainstem in AD brains will be determined in all sectors of these nuclei using immunohistochemistry for choline acetyltransferase. Then, the relationship between the loss of these cholinergic markers and the density of cortical and subcortical plaques and tangles, the density of AChE-and butyrylcholinesterase (BChE)-positive cortical plaques and tangles and the loss of AChE-positive cortical pyramidal neurons will be determined. In addition, the extent of AD-related loss in the number and size of the dopaminergic neurons of the ventral tegmental area, the noradrenergic neurons of the locus coeruleus and the serotoninergic neurons of raphe will be determined and compared to the loss observed in cholinergic neurons of the basal forebrain and brainstem. The relationship between the loss observed in each nucleus and the density of cortical plaques and tangles as well as plaques and tangles in each nucleus will also be determined. All of these measures will be determined in each AD brain and compared to a control brain matched with it. The results will provide detailed information on the status of cholinergic neurons and axons in AD, will add to our knowledge concerning the site at which this cholinergic pathology is initiated and therefore will have important implications for the strategies chosen for drug therapy in AD. Further studies will determine experimentally, the effect of loss of cortical neurons on the cholinergic system. Adult rats will receive ibotenic acid lesions of the frontoparietal cortex and hippocampus, and the effect of these lesions on the density of cortical cholinergic fibers as well as the various neurochemicals contained within the cholinergic neurons of the basal forebrain (ChAT, nerve growth factor receptors, galanin and NADPH-diapharase) determined.
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0.906 |
1994 — 1996 |
Geula, Changiz |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Cholinergic System in Alzheimers Disease @ Beth Israel Deaconess Medical Center
Although degeneration of cortical cholinergic innervation is a consistent feature of Alzheimer's disease (AD), many questions concerning the nature and origin of this degeneration remain unanswered. Of note, no comprehensive histochemical survey exists of the cholinergic system in AD. The major goal of the research outlined in this proposal is to provide a comprehensive survey of the cholinergic system in AD using histochemical and morphological methods. The existence of regional variations in the loss of cortical cholinergic fibers in AD will be determined using a histochemical method for acetylcholinesterase (AChE). the loss in number and size of the cholinergic neurons of the basal forebrain and brainstem in AD brains will be determined in all sectors of these nuclei using immunohistochemistry for choline acetyltransferase. Then, the relationship between the loss of these cholinergic markers and the density of cortical and subcortical plaques and tangles, the density of AChE-and butyrylcholinesterase (BChE)-positive cortical plaques and tangles and the loss of AChE-positive cortical pyramidal neurons will be determined. In addition, the extent of AD-related loss in the number and size of the dopaminergic neurons of the ventral tegmental area, the noradrenergic neurons of the locus coeruleus and the serotoninergic neurons of raphe will be determined and compared to the loss observed in cholinergic neurons of the basal forebrain and brainstem. The relationship between the loss observed in each nucleus and the density of cortical plaques and tangles as well as plaques and tangles in each nucleus will also be determined. All of these measures will be determined in each AD brain and compared to a control brain matched with it. The results will provide detailed information on the status of cholinergic neurons and axons in AD, will add to our knowledge concerning the site at which this cholinergic pathology is initiated and therefore will have important implications for the strategies chosen for drug therapy in AD. Further studies will determine experimentally, the effect of loss of cortical neurons on the cholinergic system. Adult rats will receive ibotenic acid lesions of the frontoparietal cortex and hippocampus, and the effect of these lesions on the density of cortical cholinergic fibers as well as the various neurochemicals contained within the cholinergic neurons of the basal forebrain (ChAT, nerve growth factor receptors, galanin and NADPH-diapharase) determined.
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0.906 |
1997 |
Geula, Changiz |
P51Activity Code Description: To support centers which include a multidisciplinary and multi-categorical core research program using primate animals and to maintain a large and varied primate colony which is available to affiliated, collaborative, and visiting investigators for basic and applied biomedical research and training. |
Effects of Amyloid On Aged Monkey Brain @ Harvard University (Medical School)
nervous system; Primates; Mammalia; aging;
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0.942 |
1999 — 2002 |
Geula, Changiz |
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. |
Calbindin and Cholinergic Neurons in Aging and Ad @ Beth Israel Deaconess Medical Center
DESCRIPTION: (Applicant's Abstract) The cholinergic neurons of the basal forebrain (BFCN) within the mammalian brain comprise a large neuronal system with diffuse cortical projections. A substantial body of evidence has shown that these neurons are intimately involved in the processes of learning, memory and attention. Within the human brain, the BFCN are selectively vulnerable in neurodegenerative diseases that afflict the elderly, such as Alzheimer's disease (AD). This age-dependent vulnerability suggests that normal age-related changes contribute to the degeneration of these neurons. Until recently, however, no substantial changes had been reported in the BFCN in the normal aged human brain. In an earlier study, we had observed that the majority of the primate BFCN contain the calcium binding protein Calbindin-D28k (CalBP). More recently, we have discovered that the human BFCN displays a substantial and selective loss of CalBP in the process of normal aging. We hypothesize that the loss of CalBP deprives the BFCN from the ability to buffer intracellular calcium and leaves them vulnerable to neuropathologic processes that increase intracellular calcium and thus lead to degeneration. These studies outlined in the present proposal are aimed at providing information on the role of calbindin in the degeneration of BFCN in aging and disease. The aims of the proposed experiments are to provide more comprehensive information on the age- related loss of CalBP from the human BFCN, to determine the status of CalBP in the BFCN in neurodegenerative disease of the elderly, to investigate the pathological and molecular correlates of this loss; to determine the influence of the loss of CalBP on the degeneration of BFCN in aging and AD, and to investigate animal models in which the neuroprotective role of CalBP in the BFCN can be studied using genetic approaches. The results will have important implications for the depletion of BFCN and the concomitant memory deficit and other cognitive abnormalities in aging and neurological diseases and have the potential to lead to new therapeutic possibilities.
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0.906 |
2006 — 2007 |
Geula, Changiz |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Camki, Apoptosis and Cholinergic Neurons in Aging and Ad @ Northwestern University
[unreadable] DESCRIPTION (provided by applicant): The basal forebrain cholinergic neuronal (BFCN) system is intimately involved in the processes of learning, memory and attention. Within the human brain, the BFCN are selectively vulnerable in neurodegenerative diseases that afflict the elderly, such as Alzheimer's disease (AD). Recent preliminary observations from our laboratory indicate that the BFCN in AD display decreased expression of the gene for calmodulin kinase I (CaMKI) and increased immunoreactivity for the apoptotic protein Fas-associated death domain (FADD). It has been shown that CaMKI downregulation causes apoptosis in neurons. Thus, the downregulation of CaMKI expression in AD BFCN may be associated with apoptosis in these neurons. We have also observed that the BFCN display a substantial loss of the calcium binding protein calbindin-D28K (CB) in the course of normal aging in the human and a further decrease in Alzheimer's disease and that the BFCN which degenerate in Alzheimer's disease appear to be those which lose this protein in the course of normal aging. We hypothesize that downregulation of CaMKI in aging and AD BFCN results in upregulation of pro-apoptotic and / or downregulation of anti- apoptotic genes, and that changes in the expression of the above genes may be related to the age-related loss of CB, which is the earliest change observed in these neurons and may result in calcium dysregulation. The experiments in this proposal are intended to expand the scope of our previous studies using more novel methodologies. The proposed experiments will test the hypotheses that using single cell laser capture microscopy combined with quantitative real time PCR analysis : A. The BFCN in aging and Alzheimer's disease will display reduced expression of genes for CaMKI and the cyclic AMP response element binding protein (CREB), increased expression of pro-apoptotic genes and / or decreased expression of anti-apoptotic genes; B. altered expression of the above genes will occur primarily in CB-negative BFCN; C. decreased expression of CaMKI in cultured mouse BFCN using small inhibitory RNA will result in similar alterations in apoptosis- related genes; and D. increased expression of CB using adeno-associated viral vectors will result in upregulation of CaMKI. The results will have important implications for selective depletion of BFCN in aging and neurological diseases. They will also form the basis of more comprehensive future studies aimed at determining the causes and effects of the alterations of the above genes. [unreadable] [unreadable] [unreadable]
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1 |
2007 — 2008 |
Geula, Changiz |
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.) |
Isolation and Characterization of Cholinesterases From Plaques and Tangles @ Northwestern University
[unreadable] DESCRIPTION (provided by applicant): It has been over two decades since it was demonstrated using histochemical methods that plaques and tangles, the pathological hallmarks of Alzheimer's disease (AD), contain activity specific to cholinergic enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The same methodology demonstrated that these AD-related cholinesterases (AD-ChE) possess different properties when compared with cholinesterases found in normal neuronal cell bodies and axons, are likely to originate in glial cells and may possess unusual activities. Biochemical studies have indicated that ChEs may be involved in the pathology of AD, particularly as it relates to the genesis of plaques and production of their main constituent, the amyloid- (A) peptide. It has been suggested that in addition to current ChE inhibitor therapies aimed at ameliorating the cortical cholinergic deficit in AD, it would also be desirable and perhaps more beneficial to inhibit ChEs in plaques and tangles, due to their possible participation in the disease process. However, research regarding the ChEs in plaques and tangles is currently at a stand-still because the only methods to date that have allowed distinction between AD-ChEs and normal ChEs are based on histochemical demonstration of activity in tissue sections. There is no method available to specifically isolate ChEs from plaques and tangles. Therefore, there is no direct information on the biochemical properties of AD-ChEs and whether they make a specific contribution to disease pathology. Furthermore, the development and pre-clinical testing of ChE inhibitors that can specifically target AD-ChEs requires a method which can isolate these enzymes from tissue. Taking advantage of recent observations at our laboratory, the fact that some ChEs are anchored to tissues (such as muscle) with the aide of extracellular matrix proteins heparan sulphate proteoglycans (HSPG) and that HSPG are also present in plaques and tangles, the experiments in the present application will test two novel methods for isolation of ChEs from plaques, tangles and glia. The specific aims of the proposed research will test the following hypotheses: 1. Cholinesterases from plaques, tangles and glial cells but not neurons and axons in fixed and fresh frozen tissue sections will be passively released into storage buffer over time. 2. Cholinesterases from plaques, tangles and glial cells but not neurons and axons in fixed and fresh frozen tissue will be released upon treatment with various glycosaminoglycans, heparinases or proteases. 3. Released cholinesterases will display molecular and enzymatic characteristics and inhibition patterns identical to those demonstrated histochemically in plaques, tangles and glia and biochemically in AD brain. The successful isolation and characterization of AD-ChEs will allow mechanistic studies of the possible detrimental effects of these ChE species; will aide in design and testing of new inhibitors specifically targeting AD-ChEs; and, is likely to lead to investigation of AD-ChEs as biomarkers of AD in blood and CSF. Plaques and tangles of Alzheimer's disease contain the cholinergic enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with altered properties that have been suggested to participate in the disease process. However, currently there are no methods available to isolate AChE and BuChE specifically from plaques and tangles, and the present application aims to fill in this gap. The successful isolation and characterization of AChE and BuChE from plaques and tangles will allow mechanistic studies of the possible detrimental effects of these enzyme species, will aide in design and testing of new inhibitors specifically targeting cholinesterases in plaques and tangles, and is likely to lead to investigation of plaque and tangle cholinesterases as biomarkers of AD in blood and cerebrospinal fluid. [unreadable] [unreadable] [unreadable]
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1 |
2009 |
Geula, Changiz |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Fifth International Conference On Alzheimer's Disease in the Me @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): Alzheimer's disease is a major health problem and the leading cause of dementia in the Americas and Europe. There has been little work done on dementia in the Middle East. This is an important issue because of the progressive aging of the populations of the world, including the Middle East as we enter the 21st century. For example, the size of the population of Egyptians 60 years and older is expected to increase by 316% from 2000 to 2030. Also, public awareness of dementia in the Middle East is low, and in many cases demented patients do not receive medical attention. The goals of this symposium are to focus attention on neurodegenerative disorders of the aged in the Middle East, to raise scientific, medical and social awareness of these disorders, and to enhance communication between Arab and Jewish medical and scientific personnel as well as communication between Middle Eastern workers and their counterparts in other countries, particularly the US. It is anticipated that the meeting will lead to increased studies of dementia in the Middle East, a region with unique features valuable for research, including a high rate of consanguinity and smoking, relatively homogenous populations, and high fat diet. A target audience of clinicians, scientists, nurses, social workers, government representatives and other agencies, pharmaceutical and other biotechnology companies will attend the meeting to be held in Larnaca, Cyprus, May 15-17, 2009. Attendees will be from the majority of Middle Eastern countries including Bahrain, Egypt, Israel, Jordan, Lebanon, Turkey, Qatar, United Arab Emirates and Saudi Arabia. Attendees from other parts of the world will include those from Cyprus, Greece, Europe, and North America. Topics to be covered include clinical and basic science aspects of dementia, diagnoses, history, management, treatment, and ethics, with consideration of the unique cultural traditions of Arab and Jewish populations. PUBLIC HEALTH RELEVANCE: There is limited awareness concerning geriatric neurology and Alzheimer's and related disorders in the Middle East and there has been relatively limited investigation of dementia in this region. As a result, the overwhelming majority of patients who suffer from dementia in the Middle East receive no medical attention. Furthermore, the Middle Eastern populations present with unique features, such as high rate of consanguinity and smoking, valuable in investigations of dementia. The proposed conference will increase awareness concerning Alzheimer's disease and related disorders in the Middle East, will help establish networks for collaboration and information flow on this topic in the region and will promote and strengthen cross-cultural and cross-national collaborative efforts and investigations, involving links between health workers and researchers in the Middle Eastern countries on the one hand and between these individuals and their counterparts in the US, Canada and Europe on the other.
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1 |
2013 |
Geula, Changiz |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
International Conf On Alzheimer Disease and Related Disorders in the Middle East @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): Alzheimer's disease is a major health problem and the leading cause of dementia in the Americas and Europe. There has been little work done on dementia in the Middle East. This is an important issue because of the progressive aging of the populations of the world, including the Middle East. For example, the size of the population of Egyptians 60 years and older is expected to increase by 316% from 2000 to 2030. Also, public awareness of dementia in the Middle East is low, and in many cases demented patients do not receive medical attention. The goal of this proposal is to obtain support for the Sixth International Conference on Alzheimer's Disease and Related Disorders in the Middle East. The objectives of this conference are to focus attention on neurodegenerative disorders of the aged, particularly Alzheimer's Disease, in the Middle East, to raise scientific, medical and social awareness of these disorders, and to enhance communication between Arab and Jewish medical and scientific personnel as well as communication between Middle Eastern workers and their counterparts in other countries, particularly the USA. It is anticipated that the meetin will lead to increased studies of dementia in the Middle East, a region with unique features valuable for research, including a high rate of consanguinity and smoking, relatively homogenous populations, and high fat diet. The primary organizers are from Middle Eastern background and are thoroughly familiar with the cultural traditions of the region, and along with the past organizer of these conferences, have built continuing collaborative relationships with works in the Middle East. A target audience of clinicians, scientists, nurses, social workers, government representatives and other agencies, pharmaceutical and other biotechnology companies will attend the meeting to be held in Istanbul, Turkey, March 23-24, 2013. Attendees will be from the majority of Middle Eastern countries including Bahrain, Egypt, Iran, Israel, Jordan, Lebanon, Palestinian Authority, Qatar, Saudi Arabia, Syria, Tunisia, Turkey, United Arab Emirates and the West Bank and will include will include workers from Europe, North America and other parts of the world. Topics to be covered include clinical and basic science aspects of dementia, diagnoses, history, management, treatment, and ethics, with consideration of the unique cultural traditions of Arab and Jewish populations. The organizers have successfully convened five editions of this conference in the past, and based on past experience expect an even more successful sixth conference.
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1 |
2014 — 2021 |
Geula, Changiz |
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. |
Concordance of Tdp-43 Inclusions With Cortical Atrophy and Clinical Phenotype @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): Aggregation of misfolded proteins in the form of abnormal inclusions is a common feature of numerous neurodegenerative diseases. The exact relationship of these inclusions to the neurosynaptic loss is incompletely understood, particularly in frontotemporal lobar degeneration (FTLD). The major goal of this proposal is to clarify the relationship between transactivation response element DNA binding protein-43 (TDP- 43) inclusions and neuronal death in FTLD. This is important because FTLD-TDP is arguably the most frequent form of FTLD and can lead to a bewildering heterogeneity of atrophy sites and clinical phenotypes. While the past few years have witnessed dazzling advances in the genetics and cellular biology of FTLD-TDP, quantitative information on the regional distribution of TDP-43 inclusions and its relationship with disease phenotype is glaringly absent from the literature. We propose to base our investigation on the unbiased stereological quantification of abnormal TDP-43 precipitates in a unique set of autopsy specimens from patients with known patterns of regional atrophy and clinical phenotypes. The central goal will be to infer the putative causes of cell death in these specimens. The hypotheses that will emerge from this human material will then be tested in a transgenic mouse model of abnormal TDP-43 precipitates. The application comes from an Alzheimer's Disease Center (ADC) with a focus on FTLD and a brain bank that has 118 autopsied pathologically characterized cases of FTLD with detailed clinical information. We will test the following hypotheses: 1. Regional differences in densities of TDP-43 inclusions will mirror clinical phenotype, focal atrophy patterns, distribution of neuronal and synaptic loss, and concentrations of inflammatory markers. 2. Conditionally TDP-43 overexpressing mice will display age-dependent behavioral abnormalities related to accumulation of cortical TDP-43 inclusions, neuronal and synaptic loss and concentration of inflammatory markers. 3. The known circuitry of the hippocampal dentate gyrus and its predilection to TDP-43 inclusions will reveal potential anterograde axodendritic and transsynaptic spread of neuropathology in human brains with FTLD-TDP pathology and in conditionally TDP-43 overexpressing mice. Histological, immunohistochemical, unbiased stereological quantitative methods and optical density measures will be used to address these hypotheses. The proposed research will generate information relevant to the contribution of TDP-43-positive inclusions, not only to disease phenotype and atrophy, but also to the underlying neuronal and synaptic loss. In the long-run, this information will be relevant to therapeutic approaches targeting TDP-43.
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1 |
2014 — 2019 |
Geula, Changiz Mesulam, Marek-Marsel M Rogalski, Emily J [⬀] |
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. |
Exceptional Cognitive Aging: Neuropsychologic, Anatomic and Pathologic Correlates @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): Memory complaints are widespread among the elderly, leading to the belief that a gradual loss of intellectual ability is an inevitable part of normal aging. However, recent pilot data from our cohort of SuperAgers in their 80s and 90s suggest that it is possible to have memory test scores at or above the average range for healthy individuals at least 20 to 30 years their junior. Our preliminary data demonstrate that SuperAgers, the focus of the current application, have larger cortical volumes (especially in the cingulate cortex), less prevalence of ApoE4, more von Economo neurons, and fewer markers of Alzheimer neuropathology than their cognitively average age peers. Longitudinal study of larger subject groups and additional neuropathologic analysis is needed to build on these findings and to disentangle cause from effect as we identify factors that promote unusually successful cognitive aging. This application will study a group of octo- and nona-genarians who have memory performance at least at an average level for individuals in their 50s and 60s in order to differentiate the inevitable consequences of time from the cumulative but preventable impact of stochastic phenomena embedded within time. Thus far, 34 SuperAgers and 10 normal agers have completed initial visits (including blood samples), >50% of these subjects have longitudinal data, 100% have agreed to or are considering brain donation, and two individuals have expired and donated their brains, demonstrating the feasibility of following this unusual cognitive aging cohort. This multidisciplinary study will take place in a setting ideally suited for this project, ith an established team of investigators with expertise in cognitive neuroscience and neuroimaging, behavioral neurology, neuropathology and neuroscience, neuropsychology, biostatistics and MR physics. The Northwestern AD Center, funded by the NIA, will support recruitment and collection of additional data. The Specific Aims of the proposed research will: 1) Establish the longitudinal phenotype of SuperAgers through neuropsychological performance as well as MR and amyloid PET imaging. 2) Investigate the prevalence and density of age-related plaque and tangle accumulation, status of basal forebrain cholinergic system and neuronal number in SuperAgers. 3) Establish a resource of behavioral and biological data for further resource sharing and collaborative investigations of SuperAgers. By identifying neurobiologic features that contribute to high memory performance in SuperAgers, it may be possible to help elderly avoid disease and disability, improve quality of life and alleviate a looming public health crisis.
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1 |
2014 — 2015 |
Geula, Changiz |
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.) |
Generation of High Passage and Immortalized Human Microglia Cell Lines @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): The goal of the proposed research is to generate and extensively characterize high passage and immortalized adult human microglia cell lines. High yield and well characterized adult human microglia cultures from each case will be necessary for mechanistic in vitro studies. Availability of large numbers of cells would also allow initial testing of drugs that can regulate microglial functions and permit isolation of large amounts of RNA and/or protein for transcriptomic or proteomic studies. Microglia have diverse functions in the healthy and diseased brain. A great deal of what has been learned regarding microglia biology is based on in vitro studies the overwhelming majority of which used cells isolated from the rodent brain. However, higher anatomical and functional complexity of the human brain and species differences in microglia response and function make imperative the use of human microglia to ascertain that the results obtained are applicable to man. Furthermore, investigation of microglia functions in the adult brain, in which many inflammatory and anti- inflammatory microglia responses occur, requires use of human microglia from adult brains. Microglia cultured from embryonic human brain show substantial proliferative capacity. However, while methods for isolation of microglia from adult postmortem human brains exist, they allow only use of a limited quantity of microglia isolated and cultured from each case due to low levels of proliferation. In preliminary attempts, we have developed a method that allows culturing microglia from adult postmortem human brains to relatively high passage. Limited preliminary testing indicated that human microglia may maintain their phenotype in high passage cultures. The proposed work will attempt to generate microglia cultures of higher passage and to extensively characterize microglia phenotypes and response to different stimuli at different passages. We will also generate and extensively characterize immortalized human microglia cell lines using a well-established protocol that utilizes human telomerase reverse transcriptase. The specific aims of the proposed work will test the following hypotheses: Aim 1 - Microglia cultured from normal adult human brains of various ages and from brains of individuals with neurodegenerative disorders will proliferate to high passage in vitro. Aim 2 - High passage human microglia will maintain their phenotype, including response to various stimulants. Aim 3 - Human microglia will be successfully immortalized, and immortalized human microglia will maintain their phenotype and response to various stimulants. Successful generation and characterization of high passage and immortalized human microglia cultures will provide the scientific community with new and reliable tools for in vitro mechanistic studies of human microglia function in health from childhood to old age, and in disease, including our own studies of microglia function in Alzheimer's disease.
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1 |
2016 |
Geula, Changiz |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
7th Intern Conf On Ad and Related Disorders in the Middle East @ Northwestern University At Chicago
Project Summary Alzheimer?s disease is a major health problem and the leading cause of dementia in the Americas and Europe. There has been little work done on dementia in the Middle East. This is an important issue because of the progressive aging of the populations of the world, including the Middle East. For example, the size of the population of Egyptians 60 years and older is expected to increase by 316% from 2000 to 2030. Also, public awareness of dementia in the Middle East is low, and in many cases demented patients do not receive medical attention. The goal of this proposal is to obtain support for the Seventh International Conference on Alzheimer?s Disease and Related Disorders in the Middle East. The objectives of this conference are to focus attention on neurodegenerative disorders of the aged, particularly Alzheimer?s disease, in the Middle East, to raise scientific, medical and social awareness of these disorders, and to enhance communication between Arab and Jewish medical and scientific personnel, and between Middle Eastern workers and their counterparts in other countries, particularly the USA. It is anticipated that the meeting will lead to increased studies of dementia in the Middle East, a region with unique features valuable for research, including a high rate of consanguinity and smoking, relatively homogenous populations, and high fat diet. Two of the organizers are from Middle Eastern background and are thoroughly familiar with the cultural traditions of the region, and along with the past organizer of these conferences, have built continuing collaborative relationships with workers in the Middle East. A target audience of clinicians, scientists, nurses, social workers, government representatives and other agencies, pharmaceutical and other biotechnology companies will attend the meeting to be held in Abu Dhabi, United Arab Emirates, November 4-6, 2016. Attendees will be from the majority of Middle Eastern countries including Bahrain, Egypt, Iran, Israel, Jordan, Lebanon, Palestinian territories, Qatar, Saudi Arabia, Syria, Tunisia, Turkey, United Arab Emirates and the West Bank and will include workers from Europe, North America and other parts of the world. Topics to be covered include clinical and basic science aspects of dementia, diagnoses, history, management, treatment, and ethics, with consideration of the unique cultural traditions of Arab and Jewish populations. The organizers have successfully convened six editions of this conference in the past, and based on past experience expect an even more successful seventh conference. The seventh conference will build on the success of the past conferences, and will feature a number of new directions, including holding the conference, for the first time, in the heart of the Middle East.
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1 |
2019 — 2021 |
Geula, Changiz |
R24Activity Code Description: Undocumented code - click on the grant title for more information. |
Characterized Adult Primary Human Microglia Cells For Research @ Northwestern University At Chicago
The goal of the proposed project is to share characterized adult primary human microglia cells of various passages from normal and diseased human brains with researchers nationally and internationally. High yield and well characterized adult human microglia cultures from our library will allow mechanistic in vitro studies with cells from the same case used in different experimental conditions. Availability of large numbers of cells would also allow initial testing of drugs that can regulate microglial functions and permit isolation of large amounts of RNA and/or protein for transcriptomic or proteomic studies. Microglia have diverse functions in the healthy and diseased brain. A great deal of what has been learned regarding microglia biology is based on in vitro studies the overwhelming majority of which used cells isolated from the rodent brain. However, higher anatomical and functional complexity of the human brain and species differences in microglia response and function make imperative the use of human microglia to ascertain that the results obtained are applicable to man. Investigation of microglia function in the adult brain, in which many inflammatory and anti-inflammatory microglia responses occur, requires use of human microglia from adult brains. Microglia cultured from embryonic human brain show substantial proliferative capacity. However, while methods for isolation of microglia from adult postmortem human brains had been described, they allowed only use of a limited quantity of microglia isolated and cultured from each case due to low levels of proliferation. We have developed a method that allows culturing microglia from adult postmortem human brains to high passage and have found that such cells maintain their phenotype in high passage cultures. We have built a library of primary adult human microglia cells of various passages from young and aged postmortem brains and from brains of individuals with various neurodegenerative disorders. The primary goal of the proposed work is to share human microglia with researchers. The specific aims of the proposed work are: Aim 1 ? Disseminate information regarding availability of characterized adult primary human microglia from brains of normal young, normal aged and brains with various neurodegenerative disorders for research and share such microglia from appropriate passages with researchers nationally and internationally. Aim 2 ? Continue phenotypic characterization of human microglia cultures, including deep sequencing, and additional characterization as requested by recipients. Aim 3 ? Replenish and expand the library by culturing from additional cases and passaging microglia from existing cases. Sharing of primary adult human microglia from various cases and different passages will provide the scientific community with a new and reliable tool for in vitro mechanistic studies of human microglia function in health from childhood to old age, and in diseases of the nervous system.
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1 |
2020 — 2021 |
Geula, Changiz Mesulam, Marek-Marsel M Rogalski, Emily J [⬀] |
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. |
Cognitive Superaging: a Model to Explore Resilience and Resistance to Aging and Alzheimers Disease @ Northwestern University At Chicago
PROJECT SUMMARY/ABSTRACT: Memory complaints are widespread among the elderly and aging is a major risk factor for Alzheimer's disease (AD), leading to the impression that a gradual loss of memory ability, eventually culminating in dementia, may be a nearly universal consequence of getting old. Our studies explore an alternative aging trajectory by studying 80+ year olds, who have episodic memory performance that appears to have escaped age-related decline and that remains in the range that is at least normal for 50-60 year-olds and we have labelled `SuperAgers'. We enrolled a dedicated and unique cohort of SuperAgers and Controls committed to longitudinal assessment and brain donation at death. Our initial studies identified domain-specific biologic, psychosocial, and genetic features of the SuperAgers, including maintenance of cortical integrity (especially in the anterior cingulate), an abundance of anterior cingulate Von Economo neurons and sparse cortical Alzheimer pathology compared to their cognitively average peers. These features may contribute in part to maintenance of superior memory performance past the 8th decade of life. This Project plans to extend the characterization of the SuperAging phenotype through hypothesis-driven novel evaluations of functional brain network connectivity, regional distribution of gene expression, and integrity of dendritic, synaptic and axonal markers. The proposed project will allow us to expand our unique group of SuperAgers and cognitively average peers and address important questions related to the neurobiology of resilience and cognitive reserve. By identifying neurobiologic features that contribute to superior memory performance in old age, outcomes from this project will help isolate factors that promote successful cognitive aging and perhaps also prevent age- related brain diseases such as AD. The project's reliance on a cohort that has already been partially recruited, its longitudinal design, multidisciplinary structure, and collaboration-friendly organization increases the likelihood that consequential progress will be achieved.
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1 |
2021 |
Geula, Changiz |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Research Education Component @ Northwestern University At Chicago
PROJECT SUMMARY - RESEARCH EDUCATION COMPONENT The Northwestern ADRC, and the Mesulam Center within which it operates, have a solid tradition of mentoring and training doctoral candidates, post-doctoral fellows and junior faculty in an interactive multidisciplinary setting that provides research training through immersive activities and breadth of knowledge and skills through a significant array of didactic educational modalities related to aging and AD/ADRD. During the past cycle, the Research Education Component (REC) of the Northwestern ADRC has accrued much experience and provided research education in aging and AD/ADRD to a large number of trainees. In the next cycle, the overall goal of the Northwestern ADRC REC will be to optimize the training of a workforce to meet the nation?s biomedical, behavioral and clinical needs in aging and AD/ADRD. The REC will have a broad mandate that will interact with the activities of all other ADRC components and will be guided by the following goals: 1) Provide cross-disciplinary research education for three research associates and junior faculty per year (REC Scholars) through innovative multidisciplinary mechanisms designed to bridge the gap between clinical and basic research experience in aging and AD/ADRD, with a stipend to provide time for training. 2) Provide research education training for at least two REC Affiliates per year, similar to the training provided to REC Scholars, but without a stipend. 3) Provide immersive research experiences and didactic training for at least five students per year at various levels of education, with concentration on underrepresented minorities, as a means of enhancing the pipeline for the future workforce in AD/ADRD. In keeping with the overall theme of our ADRC, the REC program will emphasize the heterogeneity of brain aging and dementia so that basic scientists are exposed to the complexity of the clinical presentations and translate clinical findings into mechanistic studies, while clinicians appreciate the heterogeneity of the underlying biological phenomena and translate basic findings into clinical research. The REC will be leveraged by the extensive infrastructure of the Northwestern Clinical and Translational Sciences Institute (NUCATS), with an extensive array of programs, including courses in Responsible Conduct of Research (RCR), and the Northwestern University Graduate School, including the Northwestern University Interdepartmental Neuroscience Program (NUIN), and the McGaw Medical Center of Northwestern Feinberg School of Medicine, for diversity recruitment. REC will also organize the curriculum for didactic training modalities and will review the background and career aspirations of trainees in order to ensure that clinicians become exposed to basic research and basic researchers become exposed to clinical realities.
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2021 |
Geula, Changiz Mesulam, Marek-Marsel M Rogalski, Emily J [⬀] |
U19Activity Code Description: To support a research program of multiple projects directed toward a specific major objective, basic theme or program goal, requiring a broadly based, multidisciplinary and often long-term approach. A cooperative agreement research program generally involves the organized efforts of large groups, members of which are conducting research projects designed to elucidate the various aspects of a specific objective. Substantial Federal programmatic staff involvement is intended to assist investigators during performance of the research activities, as defined in the terms and conditions of award. The investigators have primary authorities and responsibilities to define research objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations and conclusions of their studies. Each research project is usually under the leadership of an established investigator in an area representing his/her special interest and competencies. Each project supported through this mechanism should contribute to or be directly related to the common theme of the total research effort. The award can provide support for certain basic shared resources, including clinical components, which facilitate the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence. |
Study to Uncover Pathways to Exceptional Cognitive Resilience in Aging (Superaging) @ Northwestern University At Chicago
PROJECT SUMMARY (Overall): The primary goal is to establish a multicenter SuperAging Consortium to identify behavioral, health, biologic, genetic, environmental, socioeconomic, psychosocial, anatomic and neuropathologic factors associated with SuperAging. These goals will be achieved through an organizational structure with 3 Cores (Administrative/Biostatistics, Clinical/Imaging, and Biospecimen/Neuropathology) and 2 Research Projects. The Consortium will enroll 500 participants across 4 US Sites located in Illinois, Wisconsin, Michigan and Georgia, and the Canadian Site in Southwest, Ontario, with a focus on the enrollment of Black SuperAgers and Cognitively Average Elderly Controls with similar demographics (Controls). The Administrative/Biostatistics Core will provide governance and fiscal oversight, maintain scientific integrity, and create a centralized biostatistics and database infrastructure to harmonize the goals and activities of the Cores, Sites, and Projects, with each other, with the NIA and with extramural collaborators. The Clinical/Imaging Core will standardize criteria for the uniform cross-site and multidisciplinary characterization of SuperAgers, streamline recruitment including that of Black participants, enter relevant information in the comprehensive database, support co-enrollment into Project 1, and encourage collaborative ventures aiming to understand the factors that promote SuperAging. The Biospecimen/Neuropathology Core will collect and bank brain tissue and blood products from SuperAging and Control cases, according to optimized procedures. It will render pathological diagnoses, quantitate selected markers of neurodegeneration and neuronal structure, coordinate the analyses of plasma biomarkers for Alzheimer's disease, and make specimens available for collaborative investigations. Project 1 will use state-of- the-art wearable technology to obtain real-time measurements in the course of everyday life to characterize quantitative parameters related to sleep, physical activity, autonomic responsivity, and social engagement to determine whether SuperAgers have relatively preserved and quantitatively determined physiologic and behavioral `complexity' compared to Controls. Project 2 will use transcriptomic, genetic, and protein profiling approaches to test the hypothesis that SuperAgers will demonstrate significant molecular differences in their central and peripheral immune and inflammatory system parameters compared to matched Control and Alzheimer's disease participants. By identifying neurobiologic features that contribute to superior memory performance in old age, outcomes from this Consortium will help isolate factors that promote successful cognitive aging and perhaps also prevent age-related brain diseases such as Alzheimer's disease.
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