Screening for enhancers of sAPPalpha

筛选 sAPPalpha 增强子

基本信息

批准号：
9265756
负责人：
Varghese John
金额：
$ 19.25万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9265756
关键词：
Abeta clearance Affinity Aging Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Model Artificial Membranes Australia Biological Assay Blood - brain barrier anatomy Brain Brain Diseases Cell Line Cell Membrane Permeability Cells Chemicals Cleaved cell Clinic Clinical Clinical Trials Cognition Cognitive Computer Simulation Country Data Dementia Development Disease Disease Progression Dose Down-Regulation Drug Kinetics Drug usage Embryo Enhancers Environment Etiology Evaluation Event Foundations Gel Generations Genetic Screening Goals Hippocampus (Brain)Human Human Amyloid Precursor Protein Impaired cognition In Vitro Infusion procedures Lead Libraries Mediating Membrane Memory Molecular Mus N-Methyl-D-Aspartate Receptors Nausea and Vomiting Neuroblastoma Neurodegenerative Disorders Neurons Oral Outcome Pathogenicity Pathologic Pathway interactions Patients Penetrance Peptides Permeability Pharmaceutical Preparations Postoperative Nausea and Vomiting Postoperative Period Probability Process Production Rattus Resource Sharing Role Senile Plaques Slice Synapses Testing Therapeutic Tissues Treatment Efficacy Tropisetron Validation alpha secretase amyloid precursor protein processing base beta secretase bioprinting brain tissue chemical genetics clinical candidate clinical development cost density excitotoxicity gamma secretase genetic approach high throughput screening improved in vitro Model in vivo insight memory retention mild cognitive impairment mouse model neuroblastoma cell novel novel strategies novel therapeutics preclinical efficacy prevent public health relevance receptor binding response screening success symptom treatment targeted treatment therapeutic development therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) currently afflicts more than 5.4 million people in the US at an estimated cost greater than $200 billion per year. Currently approved drugs offer only short-term symptomatic relief but do not alter disease progression. The neuritic plaques that are a hallmark of AD brain result from increased generation and/or decreased clearance of the amyloid beta peptide (Aβ) which originates from amyloid precursor protein (APP). APP may be processed by two pathways. In one, it undergoes sequential β-secretase and γ-secretase cleavages to generate soluble amyloid precursor protein beta (sAPPβ) and Aβ; in the other, it is cleaved by an α-secretase to generate soluble amyloid precursor protein alpha (sAPPα), a pro-cognitive peptide that may prevent AD. This project proposes to advance our previous studies that successfully identified the sAPPα-enhancer tropisetron (F03) with the goal of identifying new sAPPα-enhancers as new chemical entities (NCEs) constituting a novel class of therapeutics for AD. Our strong foundation of preliminary data indicates a high probability that the specific aims of this project can be achieved. We have had early success utilizing our iterative, hierarchical chemical-genetics screening approach in the identification of F03 - a drug used for post- operative nausea and vomiting - from a small clinical compound library. F03 was shown to consistently but modestly increase sAPPα in vitro and in vivo in a mouse model of AD, and to significantly improve memory in the AD model after four weeks of oral treatment. F03 is now in clinical trials for mild cognitive impairment (MCI) due to AD as a repurposed drug. Here, we propose utilizing our high-throughput screening (HTS) assay, iterative screening flowscheme, and the large UCLA compound library to identify compounds with sAPPα-enhancing effects greater than F03. In the primary HTS screen, "hits" that increase sAPPα will be identified. In the secondary screen, hits are validated using a second in vitro model. Prioritized hits will then be further validated by ex vivo organotypic cultue of AD model brain and brain penetrance determined by parallel artificial membrane permeability analysis (PAMPA) and in vivo pharmacokinetic (PK) analysis. Finally, we will determine the mechanisms by which hits induce sAPPα enhancement using the CEREP Bioprint profile, drug affinity responsive target stability (DARTS), in silico target ID using the similarity ensemble approach, and by a new gel-enhanced target identification approach (GET). While other new approaches to identify therapeutics for AD and MCI are under development, their clinical outcomes remain uncertain. By identifying compounds with sAPPα enhancing effects greater than F03, we may find promising NCEs for further clinical development. Perhaps most importantly, our mechanistic studies of such enhancers may further elucidate the role of sAPPα in the etiology of AD, providing new direction for therapeutic development.