Our lab develops integrated systems, sensors, & devices for research applications in:
A) Ion Channels & Receptor Structure
B) Real time 3D structure-activity of functional channels & Detection of Biomarkers
C) Nanomedicine and Targeted Drug Delivery
D) Multiscale Biomechanics
A) How Ion Channel Structures In Neurons Affect Their Activity
Amyloid Beta Peptides Form Ion Channels That Affect A Neurons Ability to Function Properly
Amyloids are misfolded proteins that underlie a series of neurodegenerative diseases, including Alzheimer’s disease, systemic diseases such as diabetes mellitus, and cystic fibrosis. Amyloid beta fibrils were once suspected to cause these diseases, but in a series of studies on cell physiology and biology, using atomic force microscopy (AFM) and biochemical assays, we have now clearly defined that small oligomeric amyloidogenic peptides induce toxicity by forming ion channels in the cell membranes of neurons . Thus protein misfolding diseases belong to the so-called “channelopathies” with defined structural features that could be used to screen, design and deliver therapeutic interventions. In collaboration with colleagues in Germany, we have shown that a novel small molecule amyloid channel blocker reverses memory loss in AD mice models.
Hemichannels: Intercellecular Connections Between Neurons That Alter Their Volume and Mechanics
Using AFM, we demonstrated that hemichannels exist naturally as independent entities. We then showed that the 3D structure of hemichannels include pore region made of hydrophobic domains , that are gated by physiological extracellular calcium activity, and serve an important physiological function: maintenance of normal cell volume and mechanics and also regulate cell fate in oxidative stress and abnormal conditions. We are now taking a system biology approach to examine the signal transduction pathways underlying the above mentioned oxidative stress induced pathophysiology.
B) Instrument Development For Biomolecular Imaging and Detection
Integration of AFM Imaging with Electrical Recording To Study The Electro-Chemical Affects of Ion Channels on Neuron Cells
Working with collaborators, we have developed technological advances centered on an atomic force microscope (AFM). We worked on a nanopore system for combined AFM and electrical recording of ion channels. We have developed custom cantilevers for combined AFM imaging and electrical recording.
Multifunctional AFM for Simultaneous Imaging and Electrical Measurements of Communication Between Neuron Cells
We are now working on developing a multifunctional AFM array for structure function imaging of live synaptic networks. The new array-atomic force microscope (AFM-array) will consist of multifunctional cantilever array with independent sensors and actuators.This will enable 1) multipoint simultaneously imaging of synaptic networks at the scales of its organization, namely, nano-to-macro scale, 2) measuring localized electrical and chemical activity, and 3) interfacing with animal and human subjects.
Early Diagnosis of Alzheimer's Disease: Using a Novel Biosensor For Highly Accurate Detection of Multiple Target Molecules Simultaneously
In the diagnosis of Alzheimer's Disease, researchers have found that multiple molecules become more or less prevalent in cerebrospinal fluid as the disease progresses. In particular, changes in the quantity of amyloid peptides and tau proteins are typical of the disease progression. We are developing a biosensor that can accurately detect these molecules by integrating optical components (diffraction grating couplers) into micro-electro-mechanical systems (MEMS). This device aims to increase sensitivity and reduce noise in detection of multi-analytes in a biological sample. By choosing unique dyes for each target analyte, the fluorescence capability can differentiate between multiple target analytes (antigens), as well as reduce noise from the non-selective adhesion of prevalent, “sticky” biomolecules found in biological fluids. At the same time, the MEMS device can be used as a microresonator whose resonance frequency varies with the added mass from antigen-antibody binding. This resonance shift detection provides an accurate quantification of individual molecules beyond what relative fluorescence signals are capable of. The combined technologies allow for highly accurate detection of multiple target molecules simultaneously.
Biosensor Capable of Single Nucleotide Polymorphism (SNP) Detection for Studying Genetic Diseases
We have developed bio-sensors consisting of a graphene field effect transistor (GFET) with a nanoscale layer of DNA nano-device. The current through the graphene shows a characteristic response to single nucleotide gene mutation (SNP). Our SNP sensing & signaling platform will facilitate the development of the miniaturized, implantable, digital, and wireless point-of-care biosensors for early detection & monitoring of life threatening human diseases. We are expanding our target bi-molecules into proteins, bacteria and others.
C) Nanomedicine: Targeted Drug Delivery
Delivery of Drugs to Specific Organs, and Sites of Interest in the Body to Minimize Side Effects, While Curing Diseases
We are expanding into the use of nanomaterials and material properties for biological sensing, diagnosis and devices, and to understand structure and properties of biological systems. We have been pursing colloidal systems, DNA, and other smart materials in this area. Our colloidal systems are intended as nanocarriers for traceable, targeted and controllable drug delivery. We have designed multifunctional silica and gold based nanocarriers with the aim of in vivo imaging, externally actuated guidance and controlled drug delivery. Superparamagnetic iron oxide is added to silica nanocarriers to enable external guidance with magnets. Gold and quantum dots are embedded in silica nanocarriers to enable optical and photoacoustic imaging. These smart nanocarriers employ biocompatible materials and have potential for controllable delivery of payloads. Most recently, we have used a pH and temperature sensitive polymer NIPAM-co-MAA to encapsulate our nanocarriers for controllable payload release. We are now developing assays to characterize the in vivo behavior of these nanocarriers.
Additionally, we have designed DNA-based nanomachines like tweezers and nanoswitches that can lend spatial and externally actuated control when integrated into complex systems.
D) Multiscale Biomechanical Studies On the Effects That Aging Has On Bone Cartilage
We have used AFM and coupled techniques to study the mechanical properties of biological systems across multiple length scales like the endothelial barrier, hemichannels and bacteria/biofilms. Most extensively, we studied the meniscus in humans and mice during aging, injury and osteoarthritis across multiple length scales from tissue to the molecular level.