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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.

抽象的该 U19 的总体目标是利用人类群体中与极端表型相关的遗传变异健康老龄化、百岁老人和超级百岁老人，识别基因和通路中的罕见变异非常重要针对人类衰老指导药物开发1,2。项目 4（旧项目 3）专注于开发治疗方法针对第一个发现的百岁老人罕见变异，包括 IGF-1R3,4、SIRT65 和 ATM 的编码变异，以及 FOXO3A、SIRT65 和 IKK/NF-kB 通路组件 RelA/p65 中的功能性非编码变体， NFKB1/p50 和 NFKB1a (IkBa)6。在之前的资助期间，我们开发了一种新型的IKK/NF-kB抑制剂， SR12343，首先进行计算机筛选，然后使用多轮结构活性关系 (SAR) NF-kB 依赖性报告细胞系7。 SR12343 可有效减少衰老和炎症，延长三种不同衰老小鼠模型的健康寿命8。我们还证明了一种已知的抑制剂 ATM，KU55933，抑制细胞培养物中的 NF-kB 活性和衰老，并减少衰老和体内炎症和延长健康寿命9,10。此外，我们最近还发现了岩藻依聚糖，一种复合硫酸盐来自褐海藻的寡糖，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 修复活性并发挥作用一种治疗药物。褐藻糖胶治疗还减少了小鼠的衰老标志并延长了健康寿命加速老化和自然老化模型。最后，我们证明了一种已知的 SMAD3 抑制剂磷酸化 SIS3 也能减少细胞培养中的衰老。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中发现的基因和通路中经过验证的变异的治疗方法。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罕见变异的化合物在上一个资助期间确定的，包括对去泛素化很重要的 USP35 和 UBE3C 分别是 E3 泛素连接酶活性、对于 DNA 修复很重要的 BLM 以及可能存在的其他罕见变体由项目 1、2 和 3 以及核心 B 识别和/或验证。此外，我们将继续识别和优化针对 SIRT6 和 IGF-1R 编码区以及非编码、调节区中罕见变异的化合物 SIRT6、SMAD3 和 FOXO3A 的变体。针对罕见变体确定的化合物将进行测试与项目 3 合作，在加速和自然衰老的小鼠模型中进行治疗活动。具体该提案的目的是： 1) 开发和优化筛选能够模拟上一个资助期间确定的功能性遗传变异和途径的影响，包括 IGF-1R、SIRT6、USP35、UBE3C 和 BLM 中的功能性稀有编码变异以及非编码调控变异 SMAD3、FOXO3A 和 SIRT6； 2) 使用已开发的测定法来筛选能够模拟的化合物已确定的功能遗传变异和途径的影响。