Mechanisms of Brain-specific Angiogenesis Inhibitor 1 (BAI1) in neural developmen

脑特异性血管生成抑制剂 1 (BAI1) 在神经发育中的作用机制

• 批准号: 8054301
• 负责人: JOSEPH G DUMAN
• 金额: $ 12.7万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8054301
• 关键词: Actins; Acute; Address; Affect; Agonist; Angiogenesis Inhibitors; Animal Model; Anxiety Disorders; Autistic Disorder; Binding; Biochemical; Biological; Biological Assay; Biophysics; Brain; Brain-Derived Neurotrophic Factor; Brain-specific Angiogenesis Inhibitor 1; Cell Adhesion; Cells; Cellular biology; Chimera organism; Chronic stress; Communities; Complex; Couples; Cultured Cells; Cytoskeleton; Data; Defect; Dendrites; Dendritic Spines; Development; Disease; Educational process of instructing; Embryo; Employee Strikes; Environment; Ethics; Excitatory Synapse; Exercise; Exhibits; Family; Fluorescence Resonance Energy Transfer; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic Models; Goals; Growth and Development function; Hippocampus (Brain); Image; Knowledge; Laboratories; Learning; Length; Life; Link; Measures; Mediating; Medical center; Medicine; Memory; Mental Depression; Mental Retardation; Mental disorders; Mentored Research Scientist Development Award; Mentors; Methods; Modeling; Molecular; Morphogenesis; Morphology; Neoplasm Metastasis; Neuraxis; Neurodegenerative Disorders; Neurons; Neurosciences; Neurotrophic Tyrosine Kinase Receptor Type 2; Pathology; Pathway interactions; Principal Investigator; Process; Proline-Rich Domain; Property; Protein Binding Domain; Proteins; Psyche structure; Public Health; Publications; RNA Interference; Rattus; Regulation; Research; Research Personnel; Research Training; Resistance; Resolution; Role; Signal Transduction; Slice; Small GTPase Activators; Structure; Synapses; T-Cell Lymphoma; Techniques; Technology; Testing; Texas; Time; Training; Traumatic Brain Injury; Traumatic Stress Disorders; Vertebral column; Work; axon guidance; career development; college; density; extracellular; hippocampal pyramidal neuron; in vivo; information processing; malformation; member; mutant; neuron development; neurotrophic factor; non-genetic; relating to nervous system; research study; response; synaptogenesis; treatment strategy

DESCRIPTION (provided by applicant) This proposal is for a K01 Mentored Research Scientist Development Award. The candidate is a postdoctoral associate with training in cell biology and biophysics. The goal of this proposal is to transition the candidate into molecular and developmental neuroscience. The candidate is working towards the establishment of a research lab studying the mechanisms of neuronal development with emphasis on signals and signal integration; these studies will be directed toward the understanding and treatment of mental disease. The research goal of this proposal is to elucidate the mechanisms by which brain angiogenesis inhibitor I (BAI1) mediates the formation of dendrites and dendritic spines. BAI1 is member of the B family of heteromeric G-protein coupled receptors (GPCRs) and possesses both an extensive extracellular segment containing thrombospondin repeats and a long cytoplasmic segment containing multiple potential signaling domains flanking the central GPCR moiety. The candidate's preliminary data demonstrate that (1) BAI1 is critical for the proper formation of dendrites and dendritic spines in hippocampal pyramidal neurons, (2) BAI1 interacts with Tiam1, an activator of the small GTPase Rac that links extracellular signals to dendrite and spine growth and development, and (3) BAI1 affects the actin cytoskeleton, at least partially through Rac. A variety of techniques will be used (1) to determine the domain(s) of BAI1 that is (are) required to promote the development of dendrites and dendritic spines, and (2) to measure the effects of BAI1 on dendritic and spine developmental pathways involving Rac. In particular, the candidate will investigate the role of BAI1 in modulating the activation of Rac through Tiam1 in response to brain-derived neurotrophic factor through its receptor TrkB. During this time, the candidate will participate in a variety of neuroscience teaching exercises, both formal and informal. The mentoring team includes both a well-known senior neuroscientist and an exciting young investigator. This training will address the candidate's long term goal of becoming a principal investigator by providing a high-quality environment in which to learn techniques, do research, and generate publications. In addition, the candidate will benefit from career development opportunities provided by Baylor College of Medicine and his senior co-mentor, be exposed to a large variety of scientific opportunities at the Texas Medical Center, observe a laboratory being set up, and receive training in the ethical conduct of research. Both the training and research plans are facilitated by the availability of advanced imaging and other research technologies at Baylor, as well as the highly collaborative and excellent community of world-class researchers present there. PUBLIC HEALTH REVELANCE: Defects in dendrite and dendritic spine formation underlie many forms of mental disease, including autism, depression, and disorders associated with chronic stress. These defects also contribute to the pathologies of mental diseases, neurodegenerative diseases, and traumatic brain injuries. Determination of the signaling mechanisms that direct dendrite and spine formation should unveil new strategies for the treatment of these disorders.

描述（由申请人提供）本提案是K 01指导研究科学家发展奖。该候选人是一名博士后，接受细胞生物学和生物物理学方面的培训。该提案的目标是将候选人过渡到分子和发育神经科学。该候选人正在努力建立一个研究实验室，研究神经元发育的机制，重点是信号和信号整合;这些研究将针对精神疾病的理解和治疗。本研究旨在阐明脑血管生成抑制因子I（BAI 1）介导树突和树突棘形成的机制。BAI 1是异聚G蛋白偶联受体（GPCR）的B家族的成员，并且具有包含多个细胞外片段的广泛的细胞外片段， 血小板反应蛋白重复序列和含有多个潜在的信号传导结构域侧翼的中央GPCR部分的长细胞质片段。候选人的初步数据表明：（1）BAI 1对于海马锥体神经元中树突和树突棘的正确形成至关重要;（2）BAI 1与Tiam 1相互作用，Tiam 1是小GTbR Rac的激活剂，将细胞外信号与树突和棘生长和发育联系起来;（3）BAI 1至少部分通过Rac影响肌动蛋白细胞骨架。将使用多种技术（1）确定促进树突和树突棘发育所需的BAI 1结构域，以及（2）测量BAI 1对涉及Rac的树突和树突棘发育途径的影响。特别是，候选人将研究BAI 1在通过Tiam 1调节Rac激活中的作用，以响应脑源性神经营养因子通过其受体TrkB。在此期间，候选人将参加各种正式和非正式的神经科学教学练习。指导团队包括一位著名的高级神经科学家和一位令人兴奋的年轻研究者。该培训将通过提供一个高质量的环境来学习技术，进行研究和发表论文，从而实现候选人成为主要研究者的长期目标。此外，候选人将受益于贝勒医学院和他的高级共同导师提供的职业发展机会，接触到各种各样的科学机会， 在德克萨斯州医学中心，观察实验室的建立，并接受研究道德行为的培训。培训和研究计划都得益于贝勒大学先进的成像和其他研究技术，以及世界级研究人员的高度协作和优秀社区。 公共卫生部门：树突和树突棘形成缺陷是许多精神疾病的基础，包括自闭症、抑郁症和与慢性压力相关的疾病。这些缺陷也导致精神疾病、神经退行性疾病和创伤性脑损伤的病理学。直接树突和棘形成的信号机制的确定应该揭示治疗这些疾病的新策略。