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.

项目总结

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.