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

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

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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.

摘要该U19的总体目标是使用与极端表型有关的人群中的遗传变异健康衰老，百岁老人和超中心人，以识别基因和途径中的稀有变体为了指导药物开发1,2。项目4（旧项目3）专注于开发治疗针对第一个确定的百年稀有变体，包括IGF-1R3,4，SIRT65和ATM中的编码变体 FOXO3A，SIRT65和IKK/NF-KB途径的组件中的功能性非编码变体，rela/p65， NFKB1/P50和NFKB1A（IKBA）6。在上一个资金期间，我们开发了一种新颖的IKK/NF-KB抑制剂， SR12343，首先是在计算机筛选中，然后使用多轮结构活动关系（SAR）使用 NF-KB依赖性记者细胞系7。 SR12343可有效减少感应和注射，在三种不同的老年型老鼠模型中扩展健康范围。我们还证明了已知的抑制剂 ATM，KU55933，在细胞培养中抑制NF-KB活性和感应，感应降低，炎症和延长的HealthSpan在Vivo9,10中。此外，我们最近确定了富谷甘油，这是一种复杂的硫酸盐棕色海藻的寡糖，能够刺激单腺苷5'-二磷酸（ADP） - SIRT6的核糖基转移酶（MADPRT）活性刺激SIRT6依赖性DNA修复活性和功能为一种替代性。 fucoidan处理还减少了小鼠的感应和扩展健康的标记加速和自然衰老的模型。最后，我们证明了已知的Smad3抑制剂磷酸化SIS3，也降低了细胞培养的感受。这些结果证明了我们识别的能力并优化针对人类百岁老人鉴定的基因和途径中验证变体的治疗。在这里，我们建议扩大这些努力，以识别，优化和测试针对关键稀有变体的化合物在上一个资金期间确定，包括USP35和UBE3C对于去泛启动和 E3泛素连接酶的活性分别对DNA修复和其他罕见变体很重要通过项目1、2和3和CoreB验证和/或验证。此外，我们将继续识别和优化针对SIRT6和IGF-1R编码区域中稀有变体的化合物以及非编码的调节 SIRT6，SMAD3和FOXO3A中的变体。鉴定靶向稀有变体的化合物将进行测试在加速和自然衰老的小鼠模型中，与项目3合作的治疗活动。具体该提案的目的是：1）开发和优化筛选以筛选能够模仿的化合物在上一个资金期间确定的功能遗传变异和途径的影响 IGF-1R，SIRT6，USP35，UBE3C和BLM的功能稀有编码变体以及非编码调节变体在smad3，foxo3a和sirt6中； 2）使用开发的测定法筛选能够模仿的化合物鉴定出的功能遗传变异和途径的影响。