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Development of novel therapeutics targeting the identified pathways associated with human longevity

针对已确定的与人类长寿相关的途径开发新疗法

基本信息

批准号：
10714394
负责人：
JAN VIJG
金额：
$ 57.96万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714394
关键词：
Acceleration Adenosine Aging Apoptosis Bar Codes Binding Biodistribution Biological Assay CDKN2A gene Cell Culture Techniques Cell Line Cell Lineage Cells Centenarian Clinical Clinical Research Code Collaborations Complex DNA DNA Repair Data Development Diphosphates Drug Kinetics FDA approved FOXO3A gene Flavanol Fluorescence Resonance Energy Transfer Funding Generations Genes Genetic Code Genetic Variation Goals Human I-kappa B Proteins IGF1R gene Inflammation Investigational Drugs Lead Libraries Link Longevity Longevity Pathway Luciferases MADH3 gene Mus NF-kappa B Natural Products Nonhomologous DNA End Joining Oligosaccharides Pathologic Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Phenotype Phosphorylation Population Protac Regimen Reporter Research Seaweed Signal Pathway Signal Transduction Structure-Activity Relationship Sulfate TNFRSF5 gene Testing Time Toxicology Untranslated RNA Variant aged appropriate dose drug development drug discovery fucoidan genetic variant healthspan healthy aging helicase high-throughput drug screening homologous recombination improved in silico in vivo induced pluripotent stem cell inhibitor luminescence model organism mouse model new therapeutic target novel novel therapeutics p65 pharmacologic pre-clinical promoter rare variant screening senescence small molecule stem cells therapeutic evaluation therapeutic target ubiquitin-protein ligase

项目摘要

ABSTRACT The overall goal of this U19 is to use genetic variation in human populations linked to extreme phenotypes of healthy aging, centenarians and super-centenarians, to identify rare variants in genes and pathways important for human aging to guide drug development1,2. Project 4 (old Project 3) has focused on developing therapeutics targeting the first identified centenarian rare variants including coding variants in IGF-1R3,4, SIRT65, and ATM, and functional non-coding variants in FOXO3A, SIRT65 and components of the IKK/NF-kB pathway, RelA/p65, NFKB1/p50 and NFKB1a (IkBa)6. During the previous funding period, we developed a novel IKK/NF-kB inhibitor, SR12343, first by in silico screening followed by multiple rounds of Structure Activity Relationships (SAR) using a NF-kB-dependent reporter cell line7. SR12343 was effective in reducing senescence and inflammation and extending healthspan in three different mouse models of aging8. We also demonstrated that a known inhibitor of ATM, KU55933, suppressed NF-kB activity and senescence in cell culture and reduced senescence and inflammation and extended healthspan in vivo9,10. In addition, we recently identified fucoidan, a complex sulfated oligosaccharide from brown seaweed, as able to stimulate the mono–adenosine 5′-diphosphate (ADP)– ribosyltransferase (mADPRT) activity of SIRT6, stimulate SIRT6 dependent DNA repair activity and function as a senotherapeutic. Fucoidan treatment also reduced markers of senescence and extended healthspan in mouse models of accelerated and natural aging. Finally, we demonstrated that a known inhibitor of SMAD3 phosphorylation, SIS3, also reduced senescence in cell culture. These results demonstrate our ability to identify and optimize therapeutics targeting validated variants in genes and pathways identified in human centenarians. Here we propose to expand these efforts to identify, optimize and test compounds targeting key rare variants identified during the previous funding period, including USP35 and UBE3C important for deubiquintination and E3 ubiquitin ligase activities respectively, BLM important for DNA repair and potentially other rare variants to be identified and/or validated by Projects 1, 2 and 3 and Core B. In addition, we will continue to identify and optimize compounds targeting the rare variants in the coding regions of SIRT6 and IGF-1R and the non-coding, regulatory variants in SIRT6, SMAD3 and FOXO3A. The compounds identified targeting the rare variants will be tested for therapeutic activity in collaboration with Project 3 in mouse models of accelerated and natural aging. The Specific Aims of the proposal are: 1) To develop and optimize assays for screening for compounds able to mimic the effect of the functional genetic variants and pathways identified during the previous funding period including functional rare coding variants in IGF-1R, SIRT6, USP35, UBE3C and BLM and non-coding regulatory variants in SMAD3, FOXO3A and SIRT6; and 2) To use the developed assays for screening for compounds able to mimic the effect of the identified functional genetic variants and pathways.

摘要