BLR&D Research Career Scientist Award Application for Teresita Bellido, PhD

BLR

• 批准号: 10454217
• 负责人: Teresita M. Bellido
• 金额: --
• 依托单位: CENTRAL ARKANSAS VETERANS HLTHCARE SYS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454217
• 关键词: Address; Adipocytes; Affect; Anabolic Agents; Anabolism; Androgens; Antibodies; Apoptosis; Award; Biochemistry; Biology; Blood Circulation; Bone Diseases; Bone Marrow; Bone Surface; Bone remodeling; Book Chapters; Cell physiology; Cells; Communities; Connexin 43; Deterioration; Diabetes Mellitus; Disease; Doctor of Philosophy; Endocrinology; Estrogens; Exhibits; FDA approved; Family; Fracture; Functional disorder; General Population; Genes; Genetic; Glucocorticoids; Goals; Gonadal Steroid Hormones; Health; Healthcare; High Prevalence; Homeostasis; Hormones; Inbreeding; Inferior; Insulin-Dependent Diabetes Mellitus; Journals; Knowledge; Laboratories; Ligase; Malignant Neoplasms; Mechanical Stimulation; Mechanics; Mediating; Minerals; Molecular; Morbidity - disease rate; Multiple Myeloma; Mus; Muscle; Muscle Weakness; Muscular Atrophy; Musculoskeletal; Musculoskeletal Diseases; Musculoskeletal System; Mutation; Names; Non-Insulin-Dependent Diabetes Mellitus; Organ; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteopenia; Osteoporosis; PTH gene; Parathyroid Hormone Receptor; Patients; Peer Review; Peptides; Persons; Pharmacology; Phosphotransferases; Play; Prevalence; Production; Property; Proteins; Publishing; Receptor Signaling; Research; Resistance; Role; Science; Scientist; Seminal; Signal Pathway; Signal Transduction; Skeletal Muscle; Skeleton; Stimulus; TNFSF11 gene; Testing; Therapeutic; Therapeutic Intervention; Tissues; Travel; United States National Academy of Sciences; Ursidae Family; Veterans; Vitamin D; Work; World Health; antagonist; bisphosphonate; bone; bone cell; bone fracture repair; bone fragility; bone mass; bone preservation; bone quality; bone strength; cancer cell; career; cell growth; design; diabetic; diabetic patient; falls; fracture risk; gene product; individualized medicine; inhibitor; mechanical load; mechanical stimulus; mortality; mouse model; muscle strength; notch protein; novel; novel strategies; novel therapeutic intervention; parathyroid hormone-related protein; phrases; population health; precision medicine; preservation; prevent; programs; receptor; response; skeletal; skeletal disorder; targeted treatment; therapeutic development; therapeutic target; tool

Recent advances in bone biology, to which research of my laboratory in part supported by the VA have significantly contributed, demonstrate that osteocytes (the most abundant bone cells) play a critical role in bone homeostasis by regulating the production and activity of osteoblasts and osteoclasts, the cells that form or dissolve bone, respectively. However, less is known about the function of osteocytes in bone pathophysiology. Our work showed that osteocytes are crucial target cells of parathyroid hormone (PTH) action and that activation of PTH 1 receptor (PTH1R) signaling in osteocytes increases bone formation and enhances bone remodeling, recognized features of PTH skeletal action. Osteocytic PTH1R signaling decreases the expression of Sost/sclerostin, an osteocyte-derived inhibitor of bone formation, and increases the expression of RANKL, the master inducer of osteoclast differentiation. We also showed that mice lacking the PTH1R in osteocytes exhibit decreased resorption and defective anabolic response to PTH. In more recent work, we established that the low bone mass and inferior mechanical and material properties exhibited by mice with diabetes mellitus (DM) is accompanied by decreased formation, increased resorption, and increased bone marrow adipocytes (BMAT), along with increased osteocyte apoptosis and high expression of Sost/sclerostin. Further, treatment of DM mice with a PTH related protein (PTHrP)-derived peptide (1-37), which acts through the PTH1R, corrected these changes, and activated survival signaling preventing osteocyte apoptosis. The long term goal of this research is to determine the potential of targeting osteocytes and their products for treating bone maladies. The specific goal of this proposal is to unveil the mechanisms underlying protection of skeletal deterioration by PTH1R signaling in DM. Our hypothesis is that activating PTH1R signaling in osteocytes PTH or abaloparatide (FDA-approved bone anabolic agents) counteracts the damaging actions of DM in bone by regulating osteocyte-derived factors, thus maintaining bone mass and strength, preserving osteocyte viability, and reducing BMAT. This hypothesis will be tested using murine models of established type 1 and type 2 DM, associated with low versus high insulinemia, respectively, and using pharmacologic and genetic tools to activate or inhibit PTH1R signaling, and to interfere with osteocytic gene products. We will pursue the following aims: Aim 1 will examine whether pharmacologic activation of PTH1R signaling with PTH or abaloparatide restores bone mass and strength in type 1 and type 2 DM mouse models (in inbred C57BL/6 and outbred Swiss Webster strains); and reveal underlying cellular and molecular mechanisms. Aim 2 will examine osteocyte contribution to PTH1R signaling protective action on DM bone disease, by investigating the effect of PTH or abaloparatide DM mice and control mice with deletion of the PTH1R in osteocytes (DMP1-8kb-Cre). And Aim 3 will examine the role of osteocyte-derived Wnt/βcatenin antagonists on the skeletal deterioration induced by DM, by investigating whether mice lacking Sost, Dkk1, or both in osteocytes (Sostf/f; Dkk1f/f; DMP1-8kb-Cre) or mice expressing the LRP5 high bone mass mutation pG171V (resistant to Sost- and Dkk1-mediated inhibition of Wnt-βcatenin signaling) are protected from the damaging effects of DM in bone.

骨骼生物学的最新进展，我的实验室研究部分由VA支持 显着贡献，表明骨细胞（最丰富的骨细胞）在骨骼中起关键作用 通过控制成骨细胞和破骨细胞的产生和活性，即形成或 分别溶解骨头。但是，关于骨细胞在骨骼病理生理学中的功能知之甚少。 我们的工作表明，骨细胞是甲状旁腺激素（PTH）作用的关键靶细胞，并且激活 骨细胞中PTH 1受体（PTH1R）信号传导会增加骨形成并增强骨重塑， 公认的PTH骨骼动作的特征。骨细胞PTH1R信号降低了 SOST/SCLELOSTIN，一种骨形成的骨细胞抑制剂，并增加了RankL的表达， 破骨细胞分化的主要诱导剂。我们还表明，在骨细胞中缺乏PTH1R的小鼠展示 分辨率下降和对PTH的合成代谢反应有缺陷。在最近的工作中，我们确定了低 小鼠糖尿病（DM）暴露于小鼠暴露的骨骼质量以及下等材料特性为 伴随着形成减少，分辨率增加和增加的骨髓脂肪细胞（BMAT）， 加上骨细胞凋亡增加和sost/硬化蛋白的高表达。此外，DM小鼠的治疗 与PTH相关的蛋白（PTHRP）衍生的肽（1-37）（通过PTH1R起作用）纠正了这些 变化，并激活了可预防骨细胞凋亡的存活信号传导。这项研究的长期目标 是为了确定靶向骨细胞及其产物治疗骨骼疾病的潜力。具体 该提议的目标是揭示PTH1R对骨骼定义保护的基础机制 在DM中发出信号。我们的假设是激活骨细胞或鲍帕吡啶胺中的PTH1R信号传导 （FDA批准的骨合成代谢剂）通过调节来抵消DM在骨中的破坏作用 骨细胞衍生的因素，从而保持骨骼质量和力量，保留骨细胞的生存力，并保持 减少BMAT。该假设将使用已建立的类型1和2型DM的鼠模型进行检验 分别与低胰岛素血症相比，以及使用药物和遗传工具激活 或抑制PTH1R信号传导，并干扰骨细胞基因产物。我们将追求以下目标： AIM 1将检查使用PTH或鲍帕吡啶胺还原的PTH1R信号的药物化学激活是否激活 1型和2型DM鼠标模型的骨骼质量和强度（在近交C57BL/6和近代瑞士韦伯斯特 菌株）;并揭示了潜在的细胞和分子机制。 AIM 2将检查骨细胞的贡献 PTH1R信号传导通过研究PTH或鲍巴拉肽DM的作用来保护对DM骨病的作用 在骨细胞（DMP1-8KB-CRE）中删除PTH1R的小鼠和对照小鼠。 AIM 3将检查 骨细胞衍生的Wnt/βCatenin拮抗剂在DM引起的骨骼定义中的作用，通过研究 无论是缺乏SOST，DKK1的小鼠还是在骨细胞（Sostf/f; dkk1f/f; dmp1-8kb-cre）中的小鼠，还是表达表达的小鼠 LRP5高骨质量突变PG171V（对SOST和DKK1介导的Wnt-βCatenin的抑制作用 信号传导受到保护，免受骨骼中DM的破坏作用。