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Pilot Leaders

Dr. John Oakey

Associate Professor, Department of Chemical Engineering

joakey@uwyo.edu | (307) 766-2518 | Engineering Bldg 4046

Exploring the Role of Extracellular Matrix Rigidity in Myelinogenesis

Project Summary:

Demyelinating diseases range from specific conditions such as Neuromyelitis optica that causes rapid blindness to general conditions of both the peripheral or central nervous system such as Multiple Sclerosis. This project will explore cellular mechanisms common to demyelinating diseases, which are widespread and result in the loss or reduction of sensation. Demyelination is often poorly understood but inflammation, hereditary factors, and extracellular matrix (ECM) cues play important roles. Contributing to this knowledge gap is the lack of meaningful in vitro systems with which to study myelinogenesis and demyelination. While factors that influence myelination of peripheral nerves have been extensively explored, current in vitro systems are currently limited to bulk scale systems. This project will apply microfluidic and biomaterial microfabrication platforms - newly developed in and unique to our laboratory - to produce environmental niches for the controlled, systematic in vitro study of myelinogenesis and demyelination. A well-established central nervous myelination model, combined with our extensive control over spatio-temporal biomaterial properties on subcellular length scales could lead to improved control and understanding of the critical process of myelination, both for the treatment of disease, and for future neuro-regenerative applications. This project will focus upon the fabrication of precision surrogate ECM niches to culture and observe myelination of neurons on and within substrates presenting varying matrix stiffness; the creation of zonal varying stiffness on micron length scales to observe myelination and Node of Ranvier formation; and the creation of microfluidically perfusable ECM culture platforms to delivery growth factors, drugs, and cytokines, and in which to observe myelination and demyelination.

 


 

Dr. Guanglong He                                           

Assistant Professor, School of Pharmacy

ghe@uwyo.edu | (307) 766-6637 | Health Sciences Ctr 562

The Role of Innate Immune Response in Regulating Neuro-Inflammatory Pain

Project Summary:

Neuropathic pain poses a huge burden on public health and significantly affects quality of life. Yet the current therapies are often inadequate. Therefore, there is an urgent need for a better understanding of the underlying causes of this neuropathic condition. In this pilot project, I propose to study the role of innate immune response in the pathogenesis and progression of inflammatory pain with an eye on potential immunotherapies for pain management. The project addresses an important public health concern of neuro-inflammation and associated neuropathic pain. Using a unique mouse model of innate immune deficiency (CARD9 KO), I will test the hypothesis that innate immune response signaling regulates neuro-inflammation and associated neuropathic pain.

     It is postulated that cytokines/chemokines sustain neuro-inflammation and neuropathic pain by acting on sensory cells such as Schwann cells in DRG neurons resulting in peripheral sensitization. These cytokines/chemokines further induce inflammatory cell infiltration with continuous production of pro-inflammatory molecules such as IL-1β, IL-6, TNFα, CXCL-1, and MCP-1. The major inflammatory cell types involved are neutrophils and macrophages. CARD9 is a central regulator of the innate immune response and is associated with immune cell activation and inflammatory response. CARD9 signaling plays a pivotal role in the infiltration of macrophages/neutrophils and production of cytokines/chemokines in obesity and myocardial infarction, suggesting a detrimental effect in sterile inflammation. Therefore, inhibition of CARD9 signaling would attenuate inflammatory response to nerve injury or irritant-induced inflammatory pain. The proposed study is expected to fill a knowledge gap on the mechanistic link between the CARD9 innate immune response signaling and neuropathic and inflammatory pain.

     There are two specific aims: 1) to determine the regulatory role of CARD9 innate immune signaling on peripheral sensitization of inflammatory pain induced by chemical irritants; 2) to determine if a specific IL-1beta receptor antagonist could partially recapitulate the effect of CARD9 KO and suppress the peripheral sensitization. The outcome will help develop strategies to reduce chronic inflammatory pain with an overall impact on reducing public health burden and improving quality of life. The study may also have a broad impact on other chronic pains resulting from physical nerve damage, diabetes, and chemotherapy.

 


 

Dr. Michael Taylor

Assistant Professor, Department of Chemistry

mtaylo45@uwyo.edu | (307) 766-4363 | Physical Sciences Bldg 403

New Chemical Tools for Mapping Transient Chemical Processes in Biology

Project Summary:

This proposal describes the development of a new chemical sensing technique for the detection of electron transfer (ET) and photo-induced electron transfer (PET) in cells. ET and PET are essential chemical processes in organismal sensing of both light and magnetic fields, but the transient lifetimes of PET intermediates, coupled with inconsistent correlations between genetic and behavioral studies on these sensing process have made these phenomena challenging to study directly in vivo. As such, a reagent that could be administered to cells and activated under electron transfer conditions to install a reporting label on the co-reactant would be a useful tool for studying these processes in vivo. We have designed a PET-activated reagent (PET-sense) that features the use of an N-substituted pyridinium salt that, upon acceptance of a single electron from a protein, initiates a bond forming process that installs a reporter label onto the protein donor, thus enabling the direct detection of an electron transfer process. The main objective of this proposal is to develop the PET-sense reagent into a system that labels proteins with high efficiency and then demonstrate the probe’s effectiveness at detecting electron transfer in cells. This will be accomplished in two main aims: (1) Development of a PET-sense probe for the efficient modification of tryptophan residues in complex proteins and (2) through the labeling of Drosophila S2 cells that express a cryptochrome flavoprotein. To achieve this, we will template our optimal PET-sense design from Aim 1 onto the flavin scaffold and demonstrate the selective labeling of an expressed and purified cryptochrome protein to optimize the design. We will then label the S2 cells using this optimal PET-sense probe and assess outcomes via two-photon cellular imaging using the IMcore facility as well as biotin/avidin purification.


 

Contact Us

Dr. Qian-Quan Sun, SBC director, Professor

Department of Zoology and Physiology

Laramie, WY 82071

Phone: 307-766-5602

Email: neuron@uwyo.edu

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