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Targeting Cellular Senescence and RAGE in Type 2 Diabetes

靶向 2 型糖尿病中的细胞衰老和 RAGE

基本信息

批准号：
10386884
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
项目类别：
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/10386884
关键词：
Address 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 Mutation Energy Metabolism Fatty Acids Fatty acid glycerol esters Fracture Functional disorder Genetic Genetic Transcription Histologic Hyperglycemia In Vitro Inflammation Inflammatory Intervention Intuition LOX gene Life Liver Lysine 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 Pharmacology Phenotype Physiological Processes Population Process Property Proteins Quercetin 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 pre-clinical premature prevent promoter receptor binding receptor for advanced glycation endproducts senescence skeletal sugar tool transgenic suicide gene young adult

项目摘要

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（T2 D）是骨质差和骨折的主要危险因素，与过早发生骨质疏松症有关。衰老细胞和晚期糖基化终产物（AGEs; AGE [AGE]途径）。内皮细胞、衰老细胞和内皮细胞可以起作用独立地或通过串扰相互作用，以显著地促进T2 D中的骨骼脆弱性，但是这个概念还没有经过严格的测试。这一建议是建立在创新的概念，技术和方法为了验证我们的核心假设，即靶向细胞衰老或衰老可以改善T2 D相关的骨骼肌功能，脆弱为了验证我们的假设，我们将使用新型转基因小鼠和创新技术，包括大规模流式细胞术以及先进的组织学和分子工具。骨骼能量 T2 D多年来一直是研究的主题，但很少有体内研究严格地询问了衰老细胞或T2 D骨骼功能障碍的信号传导的贡献。从翻译的观点，更好地理解衰老和骨再生之间的相互作用，产生有影响力的进展，并可能揭示改善T2 D加速骨骼衰老的新策略。到为此，在目标1中，我们将鉴定、定位和表征小鼠骨骼驻留的衰老细胞群与T2 D，并定义其T2 D特异性衰老相关分泌表型（SASP）。在目标2中，使用携带能够选择性消除p16 Ink 4a+或p21 Cip 1+衰老细胞的转基因小鼠，我们将测试在具有已建立的T2 D的小鼠中衰老细胞清除将使骨重建正常化的假设和质量因此，我们将区分p16 Ink 4a和p21 Cip 1在介导骨骼功能障碍中的因果作用，使用我们的全球p16-和p21-ATTAC小鼠品系，通过比较 p16 Ink 4a + vs p21 Cip 1+衰老细胞。此外，我们将评估清除衰老的相对影响，骨细胞，使用我们的新Cre-LoxP系- p16-LOX-ATTAC和p21-LOX-ATTAC。全球和骨细胞- 将衰老细胞的特异性清除与使用“Senolytics”的药理学消除进行比较。最后，在目的3中，使用我们的新型Cre-loxP小鼠，其通过细胞特异性的细胞内信号转导抑制BMPs信号转导。胞质结构域缺陷型显性负调控基因（DN-SSCP）的表达，我们将定义抑制成骨细胞/骨细胞和髓样/破骨细胞谱系中的信号传导， T2 D小鼠总的来说，这些研究将严格测试细胞衰老和衰老信号是否 T2 D相关的骨骼脆弱性的基础。我们将利用我们独特的资源解决这些问题，专业知识我们将建立在令人信服的初步数据和创新方法，包括新的我们预计，分析、转基因和药理学工具将大大推进我们的理解， T2 D中骨骼功能障碍的基础生物学，导致新的机制见解和证据- 基于治疗方法，以促进临床前发现转化为临床应用。