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

描述(由申请人提供)本提案是针对K01指导研究科学家发展奖。候选人是细胞生物学和生物物理学方面的博士后助理。这项提议的目标是将候选人转变为分子和发育神经科学。这位候选人正致力于建立一个研究神经发育机制的实验室，重点是信号和信号整合；这些研究将指向对精神疾病的理解和治疗。本研究的目的是阐明脑血管生成抑制因子I(BAI1)介导树突和树突棘形成的机制。BAI1是异构体G蛋白偶联受体(GPCRs)B家族的成员，具有广泛的胞外片段，包括 凝血酶反应蛋白重复序列和一个长的细胞质片段，该片段包含多个潜在的信号结构域，位于中央GPCR部分的两侧。候选人的初步数据表明：(1)BAI1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)BAI1与Tiam1相互作用，Tiam1是小GTPase Rac的激活剂，将细胞外信号与树突和脊椎的生长发育联系在一起，(3)BAI1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BAI1的结构域(S)，该结构域是促进树突和树突棘发育所必需的；(2)测量BAI1对涉及RAC的树突和脊椎发育途径的影响。特别是，候选人将研究BAI1在通过Tiam1通过其受体TrkB调节RAC对脑源性神经营养因子的反应中的作用。在此期间，候选人将参加各种神经科学教学练习，包括正式和非正式的。指导团队既包括一位知名的资深神经学家，也包括一位令人兴奋的年轻研究员。这一培训将通过提供一个学习技术、进行研究和出版出版物的高质量环境来解决候选人成为首席研究员的长期目标。此外，应聘者将受益于贝勒医学院和他的高级合作导师提供的职业发展机会，并将在 在德克萨斯医学中心，观察正在建立的实验室，并接受研究道德行为方面的培训。培训和研究计划都得益于贝勒先进的成像和其他研究技术，以及那里高度合作和优秀的世界级研究人员社区。 公共卫生评论：树突和树突形成的缺陷是许多形式的精神疾病的基础，包括自闭症、抑郁症和与慢性应激相关的障碍。这些缺陷还导致精神疾病、神经退行性疾病和创伤性脑损伤的病理。确定引导树突和棘突形成的信号机制应该会揭示治疗这些疾病的新策略。

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.