Targeting Cellular Senescence and RAGE in Type 2 Diabetes

靶向 2 型糖尿病中的细胞衰老和 RAGE

• 批准号: 10604279
• 负责人: Joshua Nicholas Farr
• 金额: $ 39.75万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604279
• 关键词: Acceleration; Advanced Glycosylation End Products; Aging; Apoptosis; B-Lymphocytes; Biology; Biomechanics; Bone Resorption; Bone remodeling; Brain; CASP8 gene; CDKN2A gene; Cell Aging; Cells; Ceramides; Collagen; Complement; Complications of Diabetes Mellitus; Cre-LoxP; Cytometry; Dasatinib; Data; Deterioration; Development; Dominant Negative Receptor; Energy Metabolism; Fatty Acids; Fatty acid glycerol esters; Fracture; Functional disorder; Genetic; Genetic Transcription; Histologic; Hyperglycemia; In Vitro; Inflammation; Inflammatory; Innate Bone Remodeling; Intervention; Intuition; LOX gene; Life; Liver; Lysine; Maps; Marrow; Mass Spectrum Analysis; Mediating; Metabolic; Metabolic dysfunction; Metabolic stress; Molecular; Mouse Strains; Mus; Myelogenous; Myeloid Cells; Non-Insulin-Dependent Diabetes Mellitus; Osteoblasts; Osteoclasts; Osteocytes; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiological Processes; Population; Process; Property; Proteins; Quercetin; Receptor Activation; Receptor Inhibition; Research; Resources; Risk Factors; Role; Serum; Signal Transduction; Skeleton; Structure of beta Cell of islet; System; T-Lymphocyte; Technology; Testing; Therapeutic; Tissues; Transgenes; Transgenic Mice; Transgenic Organisms; Translations; Work; aged; bone; bone cell; bone quality; bone turnover; cellular targeting; clinical application; diabetic; evidence base; glycation; high dimensionality; improved; in vivo; innovation; innovative technologies; insight; non-diabetic; novel; novel strategies; novel therapeutic intervention; osteoprogenitor cell; pharmacologic; pre-clinical; premature; prevent; promoter; receptor binding; receptor for advanced glycation endproducts; senescence; skeletal; sugar; tool; transgenic suicide gene; young adult

PROJECT SUMMARY Type 2 diabetes (T2D), a major risk factor for poor bone quality and fractures, is associated with the premature accumulation of senescent cells and advanced glycation endproducts (AGEs; activators of the receptor for AGE [RAGE] pathway) in multiple tissues, including bone. Intuitively, senescent cells and RAGE could act independently or interact via cross-talk to contribute substantially to skeletal fragility in T2D, yet this concept has not been rigorously tested. This proposal is founded on innovative concepts, technology, and approaches to test our central hypothesis that targeting cellular senescence or RAGE can improve T2D-related skeletal fragility. To test our hypothesis, we will use novel transgenic mice and innovative technology, including mass cytometry as well as advanced histological and molecular tools. The interplay among bone, energy metabolism, and T2D has been a topic of research for years, yet few in vivo studies have rigorously interrogated the contributions of senescent cells or RAGE signaling to skeletal dysfunction in T2D. From a translational perspective, better understanding of the cross-talk between senescence and RAGE in bone will yield impactful advances and may reveal novel strategies to ameliorate accelerated skeletal aging in T2D. To this end, in Aim 1 we will identify, locate, and characterize bone-resident senescent cell populations in mice with T2D and define their T2D-specific senescence-associated secretory phenotype (SASP). In Aim 2, using mice harboring transgenes that enable the selective elimination of p16Ink4a+ or p21Cip1+ senescent cells, we will test the hypothesis that senescent cell clearance in mice with established T2D will normalize bone remodeling and quality. Thus, we will distinguish the causal roles of p16Ink4a and p21Cip1 in mediating skeletal dysfunction in T2D using our global p16- and p21-ATTAC mouse strains by comparing the effects of systemic clearance of p16Ink4a+ vs p21Cip1+ senescent cells. In addition, we will assess the relative impact of clearing senescent osteocytes, using our novel Cre-LoxP lines – p16-LOX-ATTAC and p21-LOX-ATTAC. Global and osteocyte- specific clearance of senescent cells will be compared with pharmacological elimination using “senolytics”. Finally, in Aim 3, using our novel Cre-loxP mouse that inhibits RAGE signal transduction via cell-specific cytosolic-domain deficient dominant-negative RAGE (DN-RAGE) expression, we will define the effects of inhibiting RAGE signaling in the osteoblast/osteocyte and myeloid/osteoclast lineages on skeletal fragility in mice with T2D. Collectively, these studies will rigorously test whether cellular senescence and RAGE signaling underlie T2D-related skeletal fragility. We will address these questions by leveraging our unique resources and expertise. We will build upon compelling preliminary data and innovative approaches, including novel analytical, transgenic, and pharmacological tools that we anticipate will significantly advance our understanding of the fundamental biology of skeletal dysfunction in T2D, leading to new mechanistic insights, and evidence- based therapeutic approaches to facilitate the translation of preclinical discoveries to clinical applications.

项目摘要 2型糖尿病（T2D）是骨质质量和骨折差的主要危险因素，与早产有关 感觉细胞的积累和晚期糖基化最终产物（年龄；受体的活化剂 年龄[愤怒]途径）多次，包括骨头。直观地，感觉细胞和愤怒可以起作用 独立或通过串扰相互作用，为T2D中的骨骼脆弱性做出了重大贡献，但是这个概念 尚未经过严格测试。该建议建立在创新概念，技术和方法上 为了测试我们的中心假设，即靶向细胞感应或愤怒可以改善与T2D相关的骨骼 脆弱性。为了检验我们的假设，我们将使用新颖的转基因小鼠和创新技术，包括质量 细胞仪以及晚期的组织学和分子工具。骨骼之间的相互作用，能量 代谢和T2D多年来一直是研究的话题，但体内研究很少有严格的研究 询问了感官细胞或愤怒信号对T2D中骨骼功能障碍的贡献。来自 翻译透视，更好地理解骨头的敏感和愤怒之间的串扰 产生有影响力的进步，并可能揭示了在T2D中改善加速骨骼衰老的新型策略。到 在AIM 1中，我们将识别，定位和表征小鼠骨居民的感觉细胞种群 使用T2D并定义其T2D特异性感应相关的秘书表型（SASP）。在AIM 2中，使用 带有翻译的小鼠，可以选择性消除p16Ink4a+或p21CIP1+感觉细胞，我们将 检验以下假设，即建立T2D的小鼠的感觉细胞清除率将使骨重塑归一化 和质量。这，我们将区分p16ink4a和p21CIP1在中介骨骼功能障碍中的因果关系 T2D使用我们的全局P16和P21-ATTAC小鼠菌株通过比较全身清除的影响 P16INK4A+与P21CIP1+感觉细胞。此外，我们将评估清除感觉的相对影响 骨细胞，使用我们的新型Cre-loxp系列 - p16-lox-attac和p21-lox-attac。全球和骨细胞 将感觉细胞的特定清除与使用“鼻溶液”的药物消除进行比较。 最后，在AIM 3中，使用我们的新型Cre-loxp小鼠，该小鼠通过细胞特异性抑制愤怒信号转导 胞质有缺陷的占主导地位阴性愤怒（DN-RAGE）表达，我们将定义 抑制成骨细胞/破骨细胞和髓样/骨细胞谱系中骨骼脆弱性的愤怒信号传导 带有T2D的小鼠。总的来说，这些研究将严格测试细胞感应和愤怒信号传导是否 与T2D相关的骨骼脆弱性的基础。我们将通过利用我们独特的资源和 专业知识。我们将基于引人入胜的初步数据和创新方法，包括新颖 我们期望的分析，转基因和药品工具将大大提高我们的理解 T2D骨骼功能障碍的基本生物学，导致新的机械见解和证据 - 基于治疗方法，以促进将临床前发现转化为临床应用。

项目成果

Reference Intervals for Bone Impact Microindentation in Healthy Adults: A Multi-Centre International Study.

• DOI: 10.1007/s00223-022-01047-y
• 发表时间: 2023-03
• 期刊: CALCIFIED TISSUE INTERNATIONAL
• 影响因子: 4.2
• 作者: Rufus-Membere, Pamela;Holloway-Kew, Kara L.;Diez-Perez, Adolfo;Appelman-Dijkstra, Natasha M.;Bouxsein, Mary L.;Eriksen, Erik F.;Farr, Joshua N.;Khosla, Sundeep;Kotowicz, Mark A.;Nogues, Xavier;Rubin, Mishaela;Pasco, Julie A.
• 通讯作者: Pasco, Julie A.