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.
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 patholo- gies of mental diseases, neurodegenerative diseases, and traumatic brain injuries. Determination of the signa- ling mechanisms that direct dendrite and spine formation should unveil new strategies for the treatment of these disorders.
|Tu, Yen-Kuei; Duman, Joseph G; Tolias, Kimberley F (2018) The Adhesion-GPCR BAI1 Promotes Excitatory Synaptogenesis by Coordinating Bidirectional Trans-synaptic Signaling. J Neurosci 38:8388-8406|
|Duman, Joseph G; Mulherkar, Shalaka; Tu, Yen-Kuei et al. (2015) Mechanisms for spatiotemporal regulation of Rho-GTPase signaling at synapses. Neurosci Lett 601:4-10|
|Um, Kyongmi; Niu, Sanyong; Duman, Joseph G et al. (2014) Dynamic control of excitatory synapse development by a Rac1 GEF/GAP regulatory complex. Dev Cell 29:701-15|
|Duman, Joseph G; Tzeng, Christopher P; Tu, Yen-Kuei et al. (2013) The adhesion-GPCR BAI1 regulates synaptogenesis by controlling the recruitment of the Par3/Tiam1 polarity complex to synaptic sites. J Neurosci 33:6964-78|
|Dickson, Eamonn J; Duman, Joseph G; Moody, Mark W et al. (2012) Orai-STIM-mediated Ca2+ release from secretory granules revealed by a targeted Ca2+ and pH probe. Proc Natl Acad Sci U S A 109:E3539-48|
|Tolias, Kimberley F; Duman, Joseph G; Um, Kyongmi (2011) Control of synapse development and plasticity by Rho GTPase regulatory proteins. Prog Neurobiol 94:133-48|