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

BLR

• 批准号: 9911968
• 负责人: Teresita M. Bellido
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 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/9911968
• 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; Fracture Healing; 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; 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; bisphosphonate; bone; bone cell; 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/antagonist; mechanical load; 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退伍军人管理局的支持 显著的贡献，表明骨细胞(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实现体内平衡，这些细胞形成或 分别溶解骨骼。然而，骨细胞在骨病理生理学中的作用却知之甚少。 我们的工作表明，骨细胞是甲状旁腺激素(PTH)作用和激活的关键靶细胞 甲状旁腺素1受体(PTH1R)信号在骨细胞中的表达可促进骨形成和骨重建。 甲状旁腺素骨骼活动的公认特征。成骨细胞PTH1R信号转导途径降低蛋白表达 Sost/skerostin，一种骨形成细胞衍生的骨形成抑制因子，并增加RANKL，即 破骨细胞分化的主要诱导剂。我们还发现，在骨细胞中缺乏PTH1R的小鼠表现出 对甲状旁腺素的吸收减少和合成代谢反应缺陷。在最近的研究中，我们确定了低 糖尿病(DM)小鼠表现出的骨量和不良力学及材料性能 伴随着形成减少，吸收增加，骨髓脂肪细胞(BMAT)增加， 伴随着骨细胞凋亡率的增加和Sost/skerostin的高表达。此外，糖尿病小鼠的治疗 甲状旁腺素相关蛋白(PTHrP)衍生的多肽(1-37)通过PTH1R发挥作用，纠正了这些 改变，并激活存活信号，阻止骨细胞凋亡。这项研究的长期目标是 目的是确定靶向骨细胞及其产品治疗骨病的潜力。具体的 这项提案的目的是揭示PTH1R保护骨骼退化的潜在机制 DM中的信令。我们的假设是激活骨细胞甲状旁腺素或阿巴拉肽中的甲状旁腺素受体信号 (FDA批准的骨合成代谢药)通过调节DM在骨骼中的损害作用来中和 骨细胞衍生因子，从而维持骨量和强度，保持骨细胞活性，以及 减少BMAT。这一假设将使用已建立的1型和2型糖尿病小鼠模型进行验证， 分别与低胰岛素血症和高胰岛素血症有关，并使用药理学和遗传工具激活 或抑制PTH1R信号转导，干扰骨细胞基因产物。我们将致力于实现以下目标： 目标1将检查PTH1R信号与甲状旁腺素或阿巴拉肽的药理激活是否恢复 1型和2型糖尿病小鼠模型的骨量和强度(近交系C57BL/6和近交系瑞士Webster 菌株)；并揭示了潜在的细胞和分子机制。目标2将检查骨细胞对 PTH1R信号通路对糖尿病骨病的保护作用 小鼠和对照组小鼠骨细胞中PTH1R缺失(DMP1-8KB-Cre)。《目标3》将考察 骨细胞来源的WNT/β连接素拮抗剂对糖尿病骨骼退化的作用 无论是在骨细胞(Sostf/f；Dkk1f/f；DMP1-8KB-Cre)中缺乏SOST、Dkk1或两者的小鼠，还是表达 LRP5高骨量突变pG171V(抵抗SOST和DKK1介导的WNT-β连环蛋白抑制 信号)被保护不受骨骼中糖尿病的损害。