2006 |
Bitan, Gal |
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. |
Development Amyloid B-Protein Oligomerization Inhibitors @ University of California Los Angeles
We hypothesize that soluble amyloid beta-protein (Abeta) oligomers are key effectors of neurotoxicity and[unreadable] may be a primary cause of Alzheimer's disease (AD). Consequently, inhibition of Abeta Oligomerization[unreadable] is an attractive strategy for preventing and treating AD. We propose to use a systematic, rational[unreadable] design approach for preparation and structure-activity studies of Abeta Oligomerization inhibitors. We[unreadable] will focus our efforts on inhibitors of early Abeta(1-42) oligomers termed "paranuclei." We choose early[unreadable] Abeta(1-42) oligomers as our primary target because Abeta(1-42) is particularly linked to AD and because[unreadable] inhibition of early assembly of Abeta(1-42) will alleviate the neurotoxic effects, both of the oligomers[unreadable] themselves and of the larger neurotoxic assemblies, protofibrils and fibrils, for which paranuclei are[unreadable] precursors. Our design in based on recent experimental and modeling data that delineate structural[unreadable] features of paranucleus assembly, including primary-quaternary structure relationships and[unreadable] conformation of the C-terminus of Abeta(1-42). This region is responsible directly for the enhanced[unreadable] toxicity and distinct Oligomerization pattern of Abeta(1-42) relative to the more abundant alloform,[unreadable] Abeta(1-40). The inhibitor design process is tightly integrated with the structural and biological projects[unreadable] within the overall Program. The design process not only will benefit from the structural data[unreadable] generated by the Program members, but also will feed back into structural studies and provide[unreadable] further understanding of how particular regions and residues in Abeta interact with each other to form[unreadable] oligomers.
|
1 |
2007 — 2010 |
Bitan, Gal |
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. |
Development of Amyloid B-Protein Oligomerization Inhibitors @ University of California Los Angeles
We hypothesize that soluble amyloid beta-protein (Abeta) oligomers are key effectors of neurotoxicity and[unreadable] may be a primary cause of Alzheimer's disease (AD). Consequently, inhibition of Abeta Oligomerization[unreadable] is an attractive strategy for preventing and treating AD. We propose to use a systematic, rational[unreadable] design approach for preparation and structure-activity studies of Abeta Oligomerization inhibitors. We[unreadable] will focus our efforts on inhibitors of early Abeta(1-42) oligomers termed "paranuclei." We choose early[unreadable] Abeta(1-42) oligomers as our primary target because Abeta(1-42) is particularly linked to AD and because[unreadable] inhibition of early assembly of Abeta(1-42) will alleviate the neurotoxic effects, both of the oligomers[unreadable] themselves and of the larger neurotoxic assemblies, protofibrils and fibrils, for which paranuclei are[unreadable] precursors. Our design in based on recent experimental and modeling data that delineate structural[unreadable] features of paranucleus assembly, including primary-quaternary structure relationships and[unreadable] conformation of the C-terminus of Abeta(1-42). This region is responsible directly for the enhanced[unreadable] toxicity and distinct Oligomerization pattern of Abeta(1-42) relative to the more abundant alloform,[unreadable] Abeta(1-40). The inhibitor design process is tightly integrated with the structural and biological projects[unreadable] within the overall Program. The design process not only will benefit from the structural data[unreadable] generated by the Program members, but also will feed back into structural studies and provide[unreadable] further understanding of how particular regions and residues in Abeta interact with each other to form[unreadable] oligomers.
|
1 |
2007 — 2008 |
Bitan, Gal |
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.) |
Novel Specific Ligands For Abeta Oligomers @ University of California Los Angeles
[unreadable] DESCRIPTION (provided by applicant): This project aims to develop a novel class of molecules that interact specifically and with high affinity with neurotoxic forms of amyloid [unreadable]-protein (A[unreadable]), which are believed to cause Alzheimer's disease (AD). To date, AD has no cure and current treatments yield only moderate and temporary relief of symptoms. The clinical diagnosis of AD has sensitivity of ~85%, whereas a definite diagnosis is achieved only post mortem. Effective diagnosis and treatment for AD likely will require sensitive and specific tools for early detection of, and intervention against the neurotoxic processes that lead to development of AD. [unreadable] [unreadable] The new molecules, termed aptamers, will be selected from a library of 10(15) DNA sequences using well established methods that have been shown to yield ligands with high affinity and specificity for a large variety of targets. A difficult problem in the AD field is that the relevant targets are metastable assemblies of A[unreadable], which are difficult to study and isolate. We will overcome this difficulty employing a photochemical cross-linking technique previously developed in our laboratory to stabilize these assemblies. This method enables quantitative purification of individual assemblies. [unreadable] [unreadable] The project includes the following steps: First, aptamers with high affinity and high specificity for neurotoxic A[unreadable] assemblies will be generated. Second, we will develop an aptamer-based diagnostic technique and will use this technique to analyze cerebrospinal fluid samples from patients with AD and from healthy individuals. Third, we will assess the capability of the aptamers to inhibit the neurotoxic effect of A[unreadable] in cultures of neuronal cells as a first step towards development of aptamer-based drugs for treatment of AD. Using this systematic approach, we expect to obtain aptamers with high affinity and high specificity for the metastable, neurotoxic A[unreadable] assemblies and to use these aptamers as novel, mechanism-based tools for AD diagnostics and therapeutics. [unreadable] [unreadable] [unreadable]
|
1 |
2015 — 2019 |
Bitan, Gal |
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. |
Misfolded Protein Clearance Enhancers For Alzheimers Therapy @ University of California Los Angeles
? DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a proteinopathy characterized by deficient proteostasis of amyloid ß-protein and tau. Therefore, enhancement of clearance of the misfolded proteins involved in AD is a promising therapeutic strategy for preventing and treating the disease. We have been developing molecular tweezers (MTs) which act as Misfolded-Proteins Clearance Enhancers (MPCEs) using a unique mechanism. MTs bind to amyloidogenic proteins and remodel their abnormal self-assembly into non-toxic and non-amyloidogenic structures that can be efficiently degraded by the natural cellular clearance mechanisms. Our current lead compound, CLR01, has been found to be effective in multiple in vitro and in vivo systems, including prevention of Aß self-assembly and toxicity, inhibition of tau aggregation, and reduction of both amyloid plaques and neurofibrillary tangles in transgenic mouse brain. In addition, CLR01 was shown to have a high safety margin. However, the pharmacological characteristics of CLR01 need to be optimized, its effect on tau needs to be explored further, and certain questions about its mechanism of action and therapeutic potential are yet to be answered. In this project we will use a multi-prong approach to optimizing CLR01's pharmacokinetics, expand the characterization of its effect on tau, study CLR01's binding to amyloid plaques and neurofibrillary tangles in the brain, and characterize the capability of different doses and treatment durations of CLR01 treatment to remove toxic Aß and tau oligomers, reduce synaptotoxicity, and improve learning and memory deficits in a mouse model of AD. The study is expected to address currently unanswered questions and provide strong support for future formal development of MTs towards prevention and disease-modifying treatment of AD.
|
1 |
2016 |
Bitan, Gal |
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. |
Misfolded Protein-Clearance Enhancers For Alzheimer's Therapy @ University of California Los Angeles
? DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a proteinopathy characterized by deficient proteostasis of amyloid ß-protein and tau. Therefore, enhancement of clearance of the misfolded proteins involved in AD is a promising therapeutic strategy for preventing and treating the disease. We have been developing molecular tweezers (MTs) which act as Misfolded-Proteins Clearance Enhancers (MPCEs) using a unique mechanism. MTs bind to amyloidogenic proteins and remodel their abnormal self-assembly into non-toxic and non-amyloidogenic structures that can be efficiently degraded by the natural cellular clearance mechanisms. Our current lead compound, CLR01, has been found to be effective in multiple in vitro and in vivo systems, including prevention of Aß self-assembly and toxicity, inhibition of tau aggregation, and reduction of both amyloid plaques and neurofibrillary tangles in transgenic mouse brain. In addition, CLR01 was shown to have a high safety margin. However, the pharmacological characteristics of CLR01 need to be optimized, its effect on tau needs to be explored further, and certain questions about its mechanism of action and therapeutic potential are yet to be answered. In this project we will use a multi-prong approach to optimizing CLR01's pharmacokinetics, expand the characterization of its effect on tau, study CLR01's binding to amyloid plaques and neurofibrillary tangles in the brain, and characterize the capability of different doses and treatment durations of CLR01 treatment to remove toxic Aß and tau oligomers, reduce synaptotoxicity, and improve learning and memory deficits in a mouse model of AD. The study is expected to address currently unanswered questions and provide strong support for future formal development of MTs towards prevention and disease-modifying treatment of AD.
|
1 |
2017 — 2021 |
Bitan, Gal |
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. RF1Activity Code Description: To support a discrete, specific, circumscribed project to be performed by the named investigator(s) in an area representing specific interest and competencies based on the mission of the agency, using standard peer review criteria. This is the multi-year funded equivalent of the R01 but can be used also for multi-year funding of other research project grants such as R03, R21 as appropriate. |
Investigation of the Effect of Structural Modifications of Tau On Assembly State and Seeding @ University of California Los Angeles
Abstract (from parent application) Despite significant progress in Alzheimer?s disease (AD) in general and tau pathobiology in particular, there is still no effective treatment or prevention for AD or any other tauopathy. To develop such therapy, detailed knowledge of the structural biology and structure?activity relationship of tau is needed, including the way sequence alterations and post-translational modifications affect tau self-assembly into toxic oligomers and aggregates, and how these parameters impact tau seeding and toxicity. Here, we propose a systematic, detailed study of these aspects of tau pathology taking advantage of recent developments in mass-spectrometric, biochemical, and cell biology methods. We will study the effect of primary-structure alterations and post- translational modifications on tau oligomerization and aggregation in vitro and compare recombinant and in-vivo generated tau. We will then examine how all of these factors affect tau seeding using a recently developed highly sensitive biosensor cell line. To advance therapy development, we will also test the effect of assembly modulators on tau self-assembly and seeding. A unique aspect of the project is the combination of expertise of the PI and Co-I groups, which will allow obtaining insight into the structure?activity relationship of tau on multiple levels and answering currently pending questions about the complex processes governing this crucial aspect of AD.
|
1 |