INBRE-2 Currently Supported Research Projects
Research Themes : Cancer, Cardiovascular, Neurosciences
Research Theme - Neurosciences
Investigator: Dr. Harbinder Singh Dhillon, DSU – Biology
Mentor: Dr. Jeffrey Rosen, UD – Psychology
Research Title: Molecular Mechanisms of Learning and Memory: Investigating the role of DEL-4 in the learning behavior of Caenorhabditis elegans
Abstract: Reductionist analyses of the molecular and cellular basis of learning and memory are particularly important in understanding the neural functional design of normal human memory, as well as in age related deficits and pathological states, for example, Alzheimer’s, Parkinson’s and Huntington’s diseases. A number of invertebrate models including Aplysia californica, Drosophila melanogaster, and Caenorhabditis elegans have helped define some of the important biological substrates of behavior. In these species and others, ion channels have been shown to play important molecular roles in various neural processes including simple (e.g. mechanosensation) to complex behavior (e.g. learning and memory). Learning, which may be defined as neural plasticity in response to environmental signals, involves specific changes at synapses. The unique characteristics associated with the ion channels present in the synaptic membrane make them pivotal in understanding the basis of behavior and the plasticity of the nervous system.
Recently, behavioral neurobiologists have been focusing attention on another class of ion channels, the acid sensing ion channels (ASICs). These channels are activated by extra-cellular hydrogen ions, whose concentration is increased in the synaptic cleft upon neurotransmitter release. It is proposed that ASICs conduct cations and help regulate neurotransmitter release. These channels represent a subclass of the degenerin/epithelial Na+ channel (DEG/ENaC) superfamily of ion channels that are present in all examined multicellular eukaryotes and are most well-characterized in C. elegans. Members of the DEG/ENaC superfamily from various species show similarity in terms of their sequence and predicted topology with each individual DEG/ENaC subunit consisting of two transmembrane domains and a large extra-cellular domain. The crystal structure of a chicken ASIC has shown that it is made of three identical subunits, where there is some evidence to indicate that other ASICs may be formed of heteromeric subunits.
C. elegans, a microscopic nematode, is a well-studied model for neural network, bioimaging and genomic studies. The almost wiring of its 302 neurons is known and the complete genome of this transparent organism has been sequenced. Information from studies on the larger Deg/ENaC gene superfamily in C. elegans, makes this organism ideal for studying the structural and functional complexity of ASICs. In C. elegans genome, the DEG/ENaC superfamily comprises of 28 members, of which 7 have been characterized genetically and are implicated in mechanosensation, proprioception, and in the regulation of ultradian rhythms. The focus of this proposal is to characterize del-1, a C. elegans gene whose product is very similar in sequence to that of asic-1. Specifically, we propose to investigate the expression of del-4 using fluorescent tags, and test its potential interactions with asic-1 using fluorescence energy transfer bioimaging techniques. We have already initiated behavioral testing of a del-4 deletion mutant and our encouraging preliminary results are presented in the proposal. We expect that information obtained from using the C. elegans model will open new avenues to understanding the role of ASICs in higher organisms and provide foundations for understanding human neurological disorders.
During the course of carrying out experimentation required to accomplish the goals listed in our proposal, we plan to train undergraduate and graduate students at Delaware State University. We will also build additional capabilities in terms of carrying out sophisticated molecular biology work and develop our bioimaging facilities, while coordinating with other institutes in the state of Delaware including the core facilities available at DBI. Accomplishing the scientific and infrastructural goals will provide our group the necessary competitiveness for writing a proposal for direct federal funding by the end of year two of the proposal. The PI and the co-PI will work closely with the mentor Dr. J. Rosen from University of Delaware, for scientific discussions and guidance towards preparing a competitive NIH R01 proposal. We will also have regular electronic contact with Dr. N. Tavernarakis at the Institute of Molecular Biology and Biotechnology, whose lab is focusing on asic-1, t discuss scientific and technical issues so as to continually monitor the direction of our proposed research.
Investigator: Dr. Ilsa Gomez-Curet, Nemours
Mentor: Dr. Wenlan Wang, Nemours
Research Title: Systematic Analyses of SMN Complexes in Motor Neurons
Abstract: Spinal muscular atrophy (SMA) is an autosomal genetic disease caused by deletion or mutation(s) of the survival motor neuron gene 1 (SMN1). The hallmark of SMA is death of spinal motor neurons and muscle paralysis. SMA occurs in 1:6000 live births, and thus is one of the most common genetic causes of infant death. The long-term goal of my research is to understand the mechanism(s) of spinal motor neuron death in SMA and to develop a means to prevent neuronal cell death. Our preliminary studies show that skin fibroblasts from SMA patients display increased sensitivity to some death-promoting stimuli [1], and primary motor neuron cultures are much more sensitive to this death-promoting stimuli comparing to normal fibroblasts. This has led us to hypothesize that SMN plays a role in cell survival; increased vulnerability of motor neurons to the loss of SMN’s survival function leads to motor neuron death in SMA. The objective of this proposal is to systematically analyze composition of SMN complexes in motor neurons that are likely responsible for motor neuron survival. This could lead to answer a critical question for understanding SMA pathogenesis, which is why reduced levels of the ubiquitously expressed SMN protein selectively affect motor neurons. Here, we will leverage our expertise in cell death mechanism and motor neuron biology and cutting edge proteomics at Delaware Biotechnology Institute proteomics core directed by Dr. Kelvin Lee to dissect the SMN complexes in motor neurons. We will achieve this in the following aims: 1). We will determine the composition of SMN complexes in motor neurons. 2). We will determine distribution of SMN complexes in subcellular compartments in motor neurons. 3). We will also determine if reduced levels of SMN cause defective SMN complex formation in motor neurons. The results from the proposed studies will provide insight into the mechanism(s) by which SMN function specifically in motor neurons and how SMN-deficiency leads to SMA phenotype. Ultimately, the information obtained could lead to development of therapeutic strategies to intervene.
Investigator: Dr. Steven Most, UD Psychology
Mentor: Dr. James Hoffman UD – Psychology
Research Title: Neuro-Cognitive Self Regulation Mechanisms and Their Relation to Childhood and Adult Obesity
Abstract: Meeting benchmarks of successful weight management intervention requires that individuals make difficult choices, often involving challenging and sustained efforts of self-control. The proposed research will investigate whether individuals struggling with weight management exhibit characteristic neuro-cognitive indices related to attentional- and self-control and – because intervention often involves effortful implementation of sustained lifestyle changes – whether such indices might additionally predict intervention outcomes within a population of such individuals. The following are among the questions to be tested: (1) Do individuals struggling with weight management exhibit marked impulsiveness or difficulties involving attention shifting, working memory, and the inhibition of otherwise reflexive behaviors? Do such indices correlate with objective measures such as BMI and efficacy of intervention over the course of treatment? (2) Are weight management problems accompanied by exaggerated affectively-driven neural responses to food cues and/or by a relative inability to regulate such responses? (3) Do common food cues, such as appetitive aromas generally negatively impact cognitive control functions? These issues will be investigated through the use of objective and proven neuro-physiological and behavioral methods. It is anticipated that data obtained in the initial stages of investigation will set the stage for future funding and research, as well as for building further bridges between the University of Delaware, the A.I duPont Hospital for Children, and INBRE core centers at the Delaware Biotechnology Institute. Furthermore, this project will provide a unique training opportunity for undergraduate and graduate students wishing to work at the interface between clinical and neuro-cognitive research.
