1991 — 2001 |
Abraham, Carmela R |
P41Activity Code Description: Undocumented code - click on the grant title for more information. 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. |
Amyloidogenesis Role of Reactive Astrocytes @ Boston University Medical Campus
Arnyloidosis of the AL type, due to depositions of clonal immunoglobulin (1g) light chains, is a rare plasma cell neoplasm (2,500 new cases annually in the USA) and a rapidly progressive orphan disease with a poor prognosis. Death usually occurs 2 to 3 years after diagnosis due to organ failure despite oral therapy with melphalan and prednisone. Since July 1994, in our multidisciplinary Amyloid Program that is dedicated to finding an effective therapy forthis disease, we have treated patients in Phase I and 11 trials with intravenous (IV) melphalan (FDA END #41,776) and mobilized blood stem-cell support. Results indicate feasibility and efficacy; indeed, the therapy is so much more effective than any current treatment that it is ethically difficult to design a clinical trial to evaluate it. We are testing, therefore, in a stratified randomized prospective Phase II clinical trial, the hypothesis that treating patients within I year of diagnosis with IV melphalan and blood stem-cell support is as effective as treating patients with 2 cycles of oral therapy followed by IV melphalan. Patients are followed at 3-month intervals to assess progressive amyloidosis, plasma cell response to therapy and quality of life. In order to test thehypotheses that clonal malignant cell contamination in stem-cell collections increases with mobilization and correlates inversely with duration of response to therapy, all patients have serial marrow and blood specimens, pre- and post-mobilization blood specimens and stem-cell collections, evaluated by PCR for rearranged Ig heavy chain genes. After cloning and sequencing, responding patients amplified genetic material, tumor-specific primers are constructed in order to quantitate with competitive PCR the tumor burden in patient samples. The significance of this work lies in defining an effective therapy for this rare and rapidly fatal disease. MALDI and ESI mass spectrometry are being utilized to characterize the Ig light chain material excreted in patient urine, in order to assist in definition of the biochemical consequences of the disease and treatment.
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1997 — 1999 |
Abraham, Carmela R |
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. |
Neuroglia and Supporting Cells @ Boston University Medical Campus
We have previously identified regions of the monkey brain that exhibit morphological signs of damage with age (i.e., subcortical nuclei, white matter ) and other regions that appear relatively well-preserved (i.e., cortical grey matter). The most striking observation is the significant loss of white matter and breakdown of myelin sheaths in the aged monkey brain. Breakdown of myelin may cause aberrant transfer of information leading to cognitive deficits. We hypothesize that some of this damage seen in the cognitively impaired monkeys may be caused by the action of activated astrocytes and microglia and the dysfunction of oligodendrocytes. The goal of this project is to examine morphologically, immunocytochemically and functionally the appearance of the activated glial cells, the induction or inhibition of expression of particular mRNAs, and the production of their related proteins in those regions of the aging brain that may be involved in neurodegeneration. This project will combine morphological and quantitative assessment of all three types of glial cells from young monkeys and compare them with similar assessments in successfully aging and cognitively impaired aging monkeys. We will also perform a functional analysis of the effect of age on these cells using freshly dissected brain slices. Specifically, we will analyze the expression of inflammation-related proteins such as cytokines, complement components and inducible nitric oxide synthase, which can be detrimental to various brain cells, among them the oligodendrocytes. Differential display of cDNAs amplified from specific brain regions will be used as a complementary technique to confirm the differential expression of genes for immune system and inflammatory proteins, and to identify novel genes that are differentially expressed in the three groups of monkeys. In situ hybridization will be used to localize the messages for these genes on a cellular level. As in all projects, the animals used will be categorized according to cognitive state, so that we can determine if changes in the neuroglial cell populations and their functions are related to cognitive decline.
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2000 — 2011 |
Abraham, Carmela R |
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. P41Activity Code Description: Undocumented code - click on the grant title for more information. |
Biochemical Studies of Inflammatory Mediators and Dysmyelination @ Boston University Medical Campus
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The rhesus monkey is a model of normal human aging that enables cognitive testing to be followed by optimal preservation of brain tissue for multidisciplinary studies. These ongoing studies test the hypothesis that age-related cognitive decline results from a cascade of mild degenerative changes beginning in early middle age with inflammation and damage in white matter that leads to functional changes in axons and progresses to functional and structural changes in neurons. Three cohorts of monkeys are being studied to test various aspects of this hypothesis. After behavioral testing of the first cohort, MRI scans are followed by in vivo neurophysiology and perfusion fixation to provide fresh and fixed tissue to identify brain changes underlying cognitive decline. A second cohort of 6 middle aged monkeys is being treated like cohort 1 except their samples will be perfusion fixed with mixed aldehydes for electron microscopy to supplement existing samples and allow identification of the ultrastructural changes. A third cohort of 12 early middle aged monkeys (ages 13-15) is being followed longitudinally for with repeated behavioral testing, MRI scans of the brain, and analysis of blood and CSF. Longitudinal MRIs will reveal concurrent changes in the in vivo brain structure, and CSF and blood samples will allow biomarkers to be followed. For cohorts 1 and 3, perfusion fixation is preceded by in vivo neurophysiological assessment of compound action potentials. Two stage perfusion follows to allow immediate collection of unfixed samples from one hemisphere before the remainder of the brain is fixed. Fixed tissue is used for anatomical studies, including stereological studies of neuron numbers and immunocytochemical studies of inflammation and other degenerative processes. Structures of key proteins are being determined by FTMS and LC-MS/MS.
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2005 — 2008 |
Abraham, Carmela R |
P41Activity Code Description: Undocumented code - click on the grant title for more information. |
Determination of Binding Partners For Amyloid Precursor Protein @ Boston University Medical Campus |
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2007 — 2011 |
Abraham, Carmela R |
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. |
Biochemical Studies of Inflammatory Mediiators and Dysmyelination @ Boston University Medical Campus |
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2009 |
Abraham, Carmela R |
P41Activity Code Description: Undocumented code - click on the grant title for more information. |
Tech R&D Core Support For Aids Research @ Boston University Medical Campus
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tech R&D Core Support for AIDS Research
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2011 |
Abraham, Carmela R |
P41Activity Code Description: Undocumented code - click on the grant title for more information. |
Identify the Klotho Receptor and Its Signaling Pathway @ Boston University Medical Campus
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Klotho is an anti-aging protein with many functions involved in oxidative stress, calcium balance, insulin signaling, and cancer. Our collaborators are interested in identifying Klotho interacting proteins in the brain using Klotho-GST tagged protein with GS-pull down, to better understand the Klotho functions in the brain. We have performed a pilot experiment and identified multiple Klotho interacting proteins in HEK293 and N2a cells. Next, we will work on Klotho-GST with brain lysate.
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2016 — 2017 |
Abraham, Carmela (co-PI) Abraham, Menachem Windisch, Manfred |
R44Activity Code Description: To support in - depth development of R&D ideas whose feasibility has been established in Phase I and which are likely to result in commercial products or services. SBIR Phase II are considered 'Fast-Track' and do not require National Council Review. |
A Novel Neuroprotective Therapy For Alzheimer?S Disease @ Klogene Therapeutics, Inc.
? DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is one of the most significant public health problems of the 21st century with the number of patients in the US estimated to grow from 5 million to 15 million by 2050, and an annual cost of care projected to reach $1.1 trillion. Current treatments for AD have limited effect for a short duration, and only serve to alleviate symptoms and do not treat the underlying causes of disease. There is a pressing need to develop better therapies to relieve the cognitive impairments of the disease and delay/eliminate the need for the institutionalization of AD patients. The goal of the proposed studies is to test novel neuroprotective compounds that increase the expression of the Klotho gene and demonstrate significant cognitive improvement in animal models of AD. Loss of Klotho accelerates the development of aging-like phenotypes, including cognitive deficits, while its overexpression in mice prolongs lifespan and improves cognition. We have reported that the levels of Klotho in the brain decrease with age across species. We have further shown that: 1) pretreatment with Klotho is able to rescue primary hippocampal neurons from amyloid-? (A?) and glutamate toxicity; 2) Klotho induces oligodendrocyte differentiation and remyelination; and 3) elevating levels of Klotho enhances cognitive functions in mice, and synaptic and cognitive impairments can be prevented in the presence of A? in a transgenic mouse model that simulates key aspects of AD. These results suggested that boosting Klotho protein levels in the brain would protect it from A? and other toxic insults and prevent cognitive deterioration. As demonstration of the feasibility of this approach, a high throughput screen was conducted for small molecules that elevated Klotho expression and a series of compounds was identified that are able to penetrate the BBB and stimulate the production of Klotho within the brain. These compounds are non-polar and fulfill Lipinski's rule of 5. These drugs aim to prevent and reverse the pathogenic effects of elevated A? levels in the brain. In this Direct to Phase II proposal, Klogene Therapeutics will evaluate our top three compounds in order to determine which one would be most suitable for cognitive tests in an AD mouse model. We propose to characterize these compounds using in vitro ADMET assays, PK, and in vivo testing to determine the pharmacodynamic effect in the brain. We will choose a lead candidate and scale up compound production to perform cognitive testing in an AD mouse model. The expectation is that AD mice treated with the compound would have significant cognitive improvement. In parallel, we will identify backup compounds with potentially improved characteristics. At the successful conclusion of this Phase II SBIR, we will be poised to move forward into IND-enabling studies to support human clinical trials. The proposed studies will help bring a novel therapy to patients to treat the underlying mechanisms of AD.
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0.809 |
2016 |
Abraham, Carmela R Hodgetts, Kevin |
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. |
Discovery of Probes That Enhance Expression of the Neuroprotective Protein Klotho @ Boston University Medical Campus
Abstract Cognitive functions such as learning and memory are of fundamental biological importance and diseases that affect these functions are among the most challenging biomedical problems of our time. Just like 50% of humans suffer from cognitive decline as they age, so do the rhesus monkeys. In a long term, large study of brain changes that occur with age in these monkeys, we have shown that normal brain aging is associated with a significant downregulation of Klotho expression. We reported that the levels of the Klotho protein in the brain decrease with age across species and, interestingly, others reported earlier that loss of Klotho accelerates the development of aging-like phenotypes, including cognitive deficits, whereas Klotho overexpression extends life span. Klotho is a type 1 transmembrane pleiotropic protein predominantly expressed in kidney and brain and shed by ADAM 10 and 17 into the blood and CSF, respectively (sKlotho). While the renal functions of Klotho are well known, its roles in the brain remain to be fully elucidated. In the brain, Klotho is mainly localized in the apical plasma membrane of epithelial cells of the choroid plexus and, to a lesser extent, hippocampal neurons. In search for Klotho's function in the nervous system, we recently reported the following findings: 1) Pretreatment with sKlotho is able to protect primary hippocampal neurons from amyloid-? (A?) and glutamate toxicity. 2) sKlotho induces oligodendrocyte differentiation and remyelination. 3) In a high throughput screen, we identified small molecule compounds that increase Klotho expression. We now have lead compounds that, in vivo, elevate Klotho expression in mouse kidney and brain. 4) We recently demonstrated that increased Klotho levels are associated with enhanced cognitive functions in mice and humans and can prevent synaptic and cognitive impairments in a transgenic mouse model (hAPP mice from line J20) that simulates key aspects of Alzheimer's disease (AD). We hypothesize that small molecules capable of elevating Klotho levels (?Klotho boosters?) can enhance neural functions and prevent and reverse the pathogenic effects of elevated A? levels in the brain. To begin to test these hypotheses we need to identify Klotho boosters that will fulfill all the necessary criteria to move forward towards preclinical studies. Therefore, we propose the following specific aims: Aim 1: Optimization and in vitro characterization of the lead series of Klotho enhancing compounds (boosters) to prepare potential probes with properties predictive of good pharmacokinetics (PK) and CNS exposure. Aim 2: In vivo characterization of lead compounds to select brain-penetrant chemical probes for in vivo efficacy studies. Aim 3: Preliminary target identification using an affinity ligand strategy Increasing levels of lifespan-extending factors such as Klotho can counteract cognitive dysfunction caused by aging or neurodegenerative disease and is of utmost interest to the fields of neuroscience, aging, and neurodegeneration. The proposed study will identify the best Klotho boosters to address this fundamental question and could identify a novel therapeutic strategy for the prevention and treatment of AD.
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