Bridge Funding - Genetic variant-based drug discovery targeting conserved pathways of aging

过渡资金——针对保守的衰老途径的基于基因变异的药物发现

• 批准号: 10733650
• 负责人: JAN VIJG
• 金额: $ 44.41万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10733650
• 关键词: Administrative Supplement; Affect; Aging; Biological Assay; Candidate Disease Gene; Cardiovascular Diseases; Cell Aging; Cell model; Centenarian; DNA Damage; DNA Resequencing; Data; Diabetes Mellitus; Disease; Drug Targeting; Elderly; FOXO3A gene; Family history of; Funding; Genes; Genetic; Health; Human; Human Genetics; Individual; Insulin-Like Growth Factor I; Link; Longevity; MADH3 gene; Malignant Neoplasms; Medicine; MicroRNAs; Modeling; Molecular; Mus; NF-kappa B; Nerve Degeneration; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Physiological Processes; Research Personnel; Resources; Risk Factors; Symptoms; Testing; Therapeutic; Variant; age related; aged; cohort; college; drug development; drug discovery; embryonic stem cell; exome; genetic association; genetic resource; genetic variant; healthspan; healthy aging; human disease; human embryonic stem cell; model organism; mouse model; multiple chronic conditions; novel; novel strategies; prevent; rare variant; response; small molecule; success; therapeutic target; therapy development; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT (ADMINISTRATIVE SUPPLEMENT) Aging is the most important risk factor for common human diseases, such as diabetes, cardiovascular disease, and cancer. Hence, targeting basic mechanisms of aging rather than individual diseases is a rational strategy to develop treatments of age-related multi-morbidity. To test the validity of this approach investigators in this U19 leverage the human centenarian resource at the Albert Einstein College of Medicine to identify rare genetic variants associated with extreme human longevity to identify potential drug targets for promoting healthy aging. Using resequencing data of 400 candidate genes in 450 centenarians and 550 controls we identified, in the previous funding period, rare, functional genetic variants and associated pathways enriched in centenarians and potentially important for healthy longevity, including IGF-1, SIRT6, FOXO3A, NF-kB and SMAD3. Importantly, analysis of new, whole exome sequences of 555 centenarians and 508 controls, provided additional candidate variants, e.g., BLM, USP35, UBE3C. A number of the rare variant candidates were further characterized and evaluated functionally in human ES cells and differentiated lineages. We also generated mouse models of some of the variants for analysis of phenotypes relevant for late-life human health and subsequently used the ES cell and mouse model results as leads for developing assays and testing small molecules targeting the pathways affected by these rare variants. Interestingly, many of the rare variants and/or affected pathways could be linked to the DNA damage response, including cellular senescence. Based on the demonstrated success of our approach we now have expanded our whole exome-sequenced cohort to increase robustness of the analysis, identify additional variants and study candidate pathways through RNA-seq, functionalize additional candidate variants in ESCs and generate more mouse models. This should allow us to greatly extend the number of validated therapeutic targets for drug development.

项目摘要/摘要（行政补充）

项目成果

Senescent intervertebral disc cells exhibit perturbed matrix homeostasis phenotype.

• DOI: 10.1016/j.mad.2017.08.007
• 发表时间: 2017-09
• 期刊: Mechanisms of ageing and development
• 影响因子: 5.3
• 作者: Ngo K;Patil P;McGowan SJ;Niedernhofer LJ;Robbins PD;Kang J;Sowa G;Vo N
• 通讯作者: Vo N

Development of novel NEMO-binding domain mimetics for inhibiting IKK/NF-κB activation.

• DOI: 10.1371/journal.pbio.2004663
• 发表时间: 2018-06
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Zhao J;Zhang L;Mu X;Doebelin C;Nguyen W;Wallace C;Reay DP;McGowan SJ;Corbo L;Clemens PR;Wilson GM;Watkins SC;Solt LA;Cameron MD;Huard J;Niedernhofer LJ;Kamenecka TM;Robbins PD
• 通讯作者: Robbins PD

Mouse Models of Accelerated Cellular Senescence.

• DOI: 10.1007/978-1-4939-8931-7_17
• 发表时间: 2019
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Yousefzadeh MJ;Melos KI;Angelini L;Burd CE;Robbins PD;Niedernhofer LJ
• 通讯作者: Niedernhofer LJ