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.

骨生物学的最新进展，我的实验室的研究部分得到了 VA 的支持 显着贡献，证明骨细胞（最丰富的骨细胞）在骨骼中发挥着关键作用 通过调节成骨细胞和破骨细胞的产生和活性来维持体内平衡，这些细胞形成或 然而，人们对骨细胞在骨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) 信号传导可增加骨形成并增强骨重塑， PTH 骨骼作用的公认特征会降低骨细胞 PTH1R 信号的表达。 Sost/sclerostin 是一种骨细胞衍生的骨形成抑制剂，可增加 RANKL 的表达，RANKL 是 我们还发现，骨细胞中缺乏 PTH1R 的小鼠表现出破骨细胞分化的主要诱导剂。 在最近的工作中，我们确定了 PTH 的吸收减少和合成代谢反应缺陷。 患有糖尿病（DM）的小鼠表现出的骨量和较差的机械和材料特性是 伴随着形成减少、吸收增加和骨髓脂肪细胞（BMAT）增加， 随着骨细胞凋亡的增加和 Sost/硬化蛋白的高表达，进一步治疗 DM 小鼠。 使用 PTH 相关蛋白 (PTHrP) 衍生肽 (1-37)，通过 PTH1R 发挥作用，纠正了这些 改变并激活生存信号以防止骨细胞凋亡是本研究的长期目标。 目的是确定靶向骨细胞及其产品治疗骨疾病的潜力。 该提案的目标是揭示 PTH1R 保护骨骼退化的潜在机制 我们的假设是激活骨细胞中的 PTH1R 信号传导 PTH 或 abaloparatide （FDA 批准的骨合成代谢剂）通过调节来抵消 DM 对骨骼的破坏作用 骨细胞衍生因子，从而维持骨量和强度，保持骨细胞活力，以及 减少 BMAT 将使用已建立的 1 型和 2 型 DM 小鼠模型进行测试， 分别与低胰岛素血症和高胰岛素血症相关，并使用药理学和遗传工具来激活 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： 目标 1 将检查 PTH 或 abaloparatide 对 PTH1R 信号传导的药理学激活是否会恢复 1 型和 2 型 DM 小鼠模型（近交 C57BL/6 和远交 Swiss Webster 并揭示潜在的细胞和分子机制，目标 2 将检查骨细胞对骨细胞的贡献。 通过研究 PTH 或 abaloparatide DM 的作用，PTH1R 信号传导对 DM 骨病的保护作用 骨细胞中 PTH1R 缺失的小鼠和对照小鼠 (DMP1-8kb-Cre) 将检查骨细胞中 PTH1R 的小鼠和对照小鼠。 通过研究骨细胞衍生的 Wnt/βcatenin 拮抗剂对 DM 引起的骨骼恶化的作用 无论是骨细胞中缺乏 Sost、Dkk1 或两者 (Sostf/f; Dkk1f/f; DMP1-8kb-Cre) 的小鼠还是表达 LRP5 高骨量突变 p​​G171V（抵抗 Sost 和 Dkk1 介导的 Wnt-β 连环蛋白抑制 信号）受到保护，免受 DM 对骨骼的破坏作用。