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

• 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
• 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

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 U19的总体目标是利用与极端表型相关的人群遗传变异， 健康老龄化，百岁老人和超级百岁老人，以确定基因和重要途径的罕见变异 用于指导药物开发1，2.项目4（原项目3）专注于开发治疗方法 靶向第一个确定的百岁老人罕见变异，包括IGF-1 R3，4，SIRT 65和ATM中的编码变异， 以及FOXO 3A、SIRT 65和IKK/NF-κ B通路的组分RelA/p65中的功能性非编码变体， NFKB 1/p50和NFKB 1a（IkBa）6。在上一个资助期间，我们开发了一种新的IKK/NF-kB抑制剂， SR 12343，首先通过计算机模拟筛选，然后使用 NF-κ B依赖性报告细胞系7. SR 12343有效地减少衰老和炎症， 在三种不同的衰老小鼠模型中延长健康寿命8.我们还证明了一种已知的抑制剂， ATM，KU 55933，在细胞培养中抑制NF-kB活性和衰老，并减少衰老， 炎症和延长健康寿命在体内9，10.此外，我们最近发现了岩藻依聚糖，一种复杂的硫酸化 褐藻中的低聚糖，能够刺激单腺苷5′-二磷酸（ADP）- SIRT 6的核糖基转移酶（mADPRT）活性，刺激SIRT 6依赖性DNA修复活性，并作为 一位参议员。岩藻依聚糖硫酸酯治疗还减少了小鼠衰老的标志物并延长了健康寿命。 加速老化和自然老化模型。最后，我们证明了一种已知的SMAD 3抑制剂， 磷酸化SIS 3也减少了细胞培养物中的衰老。这些结果表明我们有能力识别 并优化针对在人类百岁老人中鉴定的基因和途径中的有效变体的治疗方法。 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 在上一个资助期内确定的，包括USP 35和UBE 3C对去泛素化很重要， E3泛素连接酶活性分别，BLM对DNA修复和潜在的其他罕见变异是重要的， 由项目1、2和3以及核心B确定和/或验证。此外，我们将继续识别和优化 靶向SIRT 6和IGF-1 R的编码区中的罕见变体以及非编码、调节区的化合物， SIRT 6、SMAD 3和FOXO 3A的变体。将对针对罕见变异体鉴定的化合物进行检测， 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性研究。具体 该提案的目的是：1）开发和优化用于筛选能够模拟 上一个资助期内确定的功能性遗传变异和途径的影响，包括 IGF-1 R、SIRT 6、USP 35、UBE 3C和BLM中的功能性罕见编码变体和非编码调节变体 SMAD 3、FOXO 3A和SIRT 6中;以及2）使用开发的测定来筛选能够模拟 所鉴定的功能性遗传变体和途径的影响。