Anne Andrews Group

­SRIs to Delay 5-HT Degeneration in AD: Effects on BDNF and Neurogenesis

Neurochip for in vivo biosensing and proteomics

The human brain represents the ultimate in biological and chemical complexity. Biological diversity is reflected by the fact that 30-50% of the genes in the human genome are largely or exclusively expressed in the brain. Chemical diversity is exemplified by the 50-100 small organic molecules thus far identified as chemical signaling molecules transmitting information between neurons and other cells. The information content of interneuronal signaling is encoded temporally and spatially on the nanoscale; therefore, one of the great challenges and potentials of the current nanotechnology revolution lies in the development of similarly scaled devices to measure rapid changes in neurotransmitter levels in specific brain regions, subregions and, ultimately, in individual synapses.

In order to investigate central nervous system interneuronal signaling at the length and time scales pertinent to its intrinsically encoded information, and ultimately, to relate this information to complex behavior, brain disorders, and new treatments and prevention strategies, chemically specific in vivo sensors are required that approach the size of a synapse (ca. 20 nm) and that respond in milliseconds. To address this daunting problem, we have developed methods to tether neurotransmitter molecules to highly optimized biospecific self-assembled monolayer surfaces. We have demonstrated that these surfaces selectively recognize large biomolecule binding partners, including antibodies and receptor proteins. One of our first goals will be to use these neurotransmitter-functionalized surfaces to capture and to identify high affinity molecular recognition elements such as those screened from nucleic acid combinatorial libraries (aptamer selection). Capture surfaces have been designed so that tethered neurotransmitters are accessible for binding beyond a dense monolayer matrix of oligoethylene glycol to minimize nonspecific binding. Tether molecules are inserted into preformed matrices to optimize surface dilution of covalently linked neurotransmitters, these probes being spaced so that each can efficiently capture large biomolecule targets. The insertion and tethering chemistries being developed are general, so that surfaces can be prepared not only for a wide range of neurotransmitters and signaling molecules (e.g. hormones) but also for other small molecule sensor applications of biological significance. Ultimately, we envision that semiconductor nanowire or carbon nanotube platforms will enable the creation of ultra small, multiplexed sensing devices having high sensitivity and fast response times, and this has the potential to revolutionize in vivo sensing.

To understand interneuronal communication, we must further address how entire neurotransmitter systems, including receptor proteins, transporters and metabolic enzymes, adapt to alterations in neurotransmission. Since the study of individual proteins and their responses in early development or to aging, stress or disease is a time-intensive analytical task, a tool to investigate functionally-related proteins as a group (both known and unknown) will also be developed using the neurotransmitter-functionalized surfaces described above8. This type of tool will allow for an extensive, simultaneous study of brain proteins that are related by their abilities to interact selectively with individual neurotransmitters. Such characterization of the dynamic expression of neurotransmitter binding proteins will enable a clearer understanding of protein regulation and signaling pathways, and their responses to environmental or genetic changes. ­Therefore, another overarching goal of this project is to interface multiplexed biospecific neurotransmitter-functionalized surfaces to mass spectrometry for the detection, structural identification, and association of functionally related proteome subsets.

Recent Publications

  1. Microcontact insertion printing. T. J. Mullen, C. Srinivasan, J. N. Hohman, S. D. Gillmor, M. J. Shuster, M. W. Horn, A. M. Andrews and P. S. Weiss, Applied Physics Letters, 90:063114-063117 (2007) (ABSTRACT or PDF).
  2. Selecting and driving monolayer structures through tailored intermolecular interactions. T. J. Mullen, A. A. Dameron, A. M. Andrews and P. S. Weiss, Aldrichimica Acta, 40:21-31 (2007) (ABSTRACT or PDF).

­Techniques Used

­
Quartz Crystal Microbalance
Surface Plasmon Resonance
Fluorescence spectroscopy and microscopy
Atomic Force Microscopy
Fourier Transform Infra-red Microscopy
­Ellipsometry



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