We study vesicle trafficking underlying neurotransmission and hormone release. We focus two major areas of research: 1) presynaptic mechanisms of transmitter release in the brain; 2) Large dense core granule trafficking in pancreatic beta cells. These studies are not only have profound impact to our current knowledge about how molecules work in human body, but also hold great promise for the development of novel rational for some severe human diseases, including neurological/psychiatric diseases and metabolic diseases (such as diabetes).
Compelling evidence suggests that many brain diseases (e.g., Alzheimer’s disease, Parkinson’s disease, epilepsy, autism, and schizophrenia) are tightly associated with alterations of synaptic function, even at the early stage of diseases. However, we have very limited understanding of neuron communication and how synapse are linked to these diseases, even we don’t know how exactly neuron processes and passes their information in healthy neural circuitry. The primary goal of my research is to understand synapses at molecule and circuit levels and how aberrant synaptic function generates/impacts neurological diseases and psychiatric disorders. The other research direction is to uncover the intracellular trafficking and dynamics of large dense core vesicles. This is directly relevant to how hormones and peptides are released and regulated in health and diseases conditions. We use pancreatic beta cells as our model cells, because dysfunction of these cells also directly link to diabetes which affects a large population of people but no cure.
My group employs multidisciplinary approaches, including cutting-edge fluorescent imaging, patch-clamp, molecular biology, and mouse models. We further actively develop innovative research tools such as super resolution optical microscopy and opto-genetic tools in live cells. The PALM (photo-activated light microscopy)/ STORM (stochastic optical reconstruction microscopy) we established in the lab has achieved a localization precision of ~16 nm, this method has almost 10 times better spatial resolution than conventional confocal microscopy.
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Fan F, Ji C, Wu Y, Ferguson SM, Tamarina N, Philipson LH, Lou X. Dynamin 2 regulates biphasic insulin secretion and plasma glucose homeostasis. J. Clin. Invest. 2015 Sep 28. pii: 80652. doi: 10.1172/JCI80652; PMID: 2641386Ji C, Zhang Y, Xu P, Xu T, and Lou X. Nanoscale Landscape of Phosphoinositides Revealed by the Specific PH-domains Using Single-molecule Super-resolution Imaging in the Plasma Membrane. J. Biol. Chem. 2015 Sep 22. pii: jbc.M115.663013. PMID: 26396197Lou X, Fan F, Messa M, Raimondi A, Wu Y, Looger LL, Ferguson SM, DeCamilli P. Reduced release probability prevents vesicle depletion and transmission failure at dynamin mutant synapses. Proc. Natl. Acad. Sci. USA, 2012 Feb 21;109(8):E515-23. PMID: 22308498.Milosevic I, Giovedi S, Lou X, Raimondi A, Collesi C, Shen H; Paradise S; O’Toole E, Ferguson S, Cremona O, De Camilli P. Recruitment of endophilin to clathrin-coated pit necks is required for efficient vesicle uncoating after fission. Neuron, 2011, 72(4):587-601. PMID: 22099461Lou X, Scheuss V, Schneggenburger R. Allosteric modulation of the presynaptic Ca2+ sensor for vesicle fusion. Nature 2005; 435(7041):497-501. PMID: 15917809.Raimondi A; Ferguson S; Lou X; Armbruster M; Paradise S; Giovedi S; Messa M; Kono N; Takasaki J; Capello; O’Toole E; Ryan T; De Camilli P. Overlapping role of dynamin isoforms in synaptic vesicle endocytosis. Neuron, 2011 Jun 23;70(6):1100-14. PMID:21689597