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Biological & Health Sciences

Developing emotional stimulation mapping to predict postoperative depression in epilepsy patients
Kelly R. Bijanki, PhD
Assistant Professor
School of Medicine
Neurosurgery
Patients with severe, treatment-resistant epilepsy undergo a diagnostic procedure to place temporary intracranial electrodes in deep brain structures to assist doctors in identifying the precise location of seizure onset. Brain activity is recorded from these electrodes and monitored for seizure activity in an intensive in-patient setting. Two commonly-implanted brain structures are the amygdala and the anterior cingulate. These structures have critical roles in emotional function, and the presence of depth electrodes allows us to record local neuronal activity as well as apply small electrical currents to stimulate for research purposes. The goal of the current research proposal is to evaluate 1) whether electrical stimulation to the amygdala and cingulate can drive measurable changes in emotional processing, and 2) whether those changes can be used to predict adverse neuropsychiatric outcomes to epilepsy surgery. This predictive ability would be potentially transformative, given that as many as 37% of patients receiving surgical treatment for severe epilepsy experience a worsening of existing depressive symptoms or the development of de novo major depressive disorder following surgery. The findings of the proposed study could help with the identification of emotion-critical brain structures in individual epilepsy patients, aiding in the development of individualized surgical plans to avoid these important regions, as a means to reduce rates of postoperative depression.

A novel in vitro germ cell model for studying trinucleotide repeat (TNR) instability in Huntington’s disease
PI:  Anthony Chan, DVM PhD
Core Scientist, Yerkes National Primate Research Center
Professor, Department of Human Genetics
Department of Pediatrics (secondary appointment)
Emory University SOM
HD is one of nine inherited polyglutamine (CAG) expansion diseases and is one of over 20human diseases caused by trinucleotide repeat (TNR) instability with increased numbers ofCAG trinucleotides through subsequent generations particularly via the male germline. WithCAG repeats above 40, individuals are at risk for developing HD. The length of the CAGtract is inversely correlated to the age of onset and is associated with onset, progression andseverity. TNR expansion also occur in somatic cells, particularly in neurons that influencedisease onset, progression and severity. It has been suggested that somatic expansion isdependent on age, while germ cell expansion is independent of age and occurs duringspermatogenesis. The proposed study is aimed to develop a novel in vitro model toreplicate TNR expansion during in vitro spermatogenesis to investigate the underlyingmechanism of expansion and retraction in humans. Our innovative model will provide a uniquein vitro platform to investigate TNR expansion in differentiating male germ cells in a dish for thefirst time, while prior studies were limited to testicular biopsy, somatic cell cultures and HDmouse models. If successful, our novel in vitro HD TNR instability model can be translated toother TNR disorders such as SCA1 with strong paternal influences. Additionally, the success ofour innovative model will also allow us to study whether extrinsic factors such as environmentaltoxicants may influence TNR instability in the paternal germline that affect future generations.

Complement Activation Mediated Acute Lung Injury in Sickle Cell Mice
PI: Satheesh Chonat, MD
Assistant Professor
School of Medicine
Department of Pediatrics
Division of Hematology/Oncology/BMT
Sickle cell disease (SCD) is a life-threatening blood disorder that affects millions of people worldwide, causing debilitating effects from acute painful episodes to chronic organ dysfunction, limiting quality of life and expectancy. Acute chest syndrome is one such acute complication, which remains a leading cause of death in patients with SCD, and currently the only available treatments include transfusions, antibiotics and oxygen therapy. We will study the mechanisms underlying complement-mediated acute lung injury and also evaluate the use of novel complement inhibitors as a potential approach to mitigate its damaging effects.

Mechanisms of Copper Induced Neurotoxicit
PI:  Avanti Gokhale, PhD
Assistant Professor
School of Medicine
Cell Biology
Parkinson’s disease is the second most prevalent neurodegenerative disease with approximately 7-10 million people affected worldwide. While several genes are implicated as causative factors for the disease the precise cellular mechanisms of disease progression remain unknown. The focus of this proposal is on the role of metal toxicity in pathology of Parkinson’s disease. Recent work has indicated a link between copper imbalances and onset as well as progression of neurodegenerative disease. Interestingly our current research has demonstrated an interaction between genes that maintain normal cellular copper levels and genes implicated in Parkinson’s disease. We propose that a rare genetic defect in the copper transporter ATP7A (involved in maintaining normal cellular copper levels) resulting in neurodegeneration forms a genetic and molecular link between metal imbalances and Parkinson’s disease mechanisms. Importantly we also predict that these copper imbalances in context of defective Parkinson’s genes specifically affect the energy production and consumption in neuronal cells.  The experimental strategies described in the proposal will test this prediction and as a result reveal novel biomarkers, risk factors and therapeutic targets for those at risk for onset of Parkinson’s disease.
 
Novel neuroprotective mechanisms against neurodegenerative diseases
PI: Lian Li, PhD
Professor and Vice Chair
School of Medicine
Department of Pharmacology
Age-related neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson disease (PD) are increasingly becoming a public health crisis worldwide. The lack of effective means of prevention or treatment for these neurodegenerative diseases emphasizes the need to identify novel neuroprotective mechanisms and therapeutic strategies. Although the etiology of age-related neurodegenerative diseases remains unknown, mitochondrial dysfunction is strongly implicated in the pathogenesis of most neurodegenerative diseases, including AD and PD. However, our knowledge of the signaling mechanisms and pathways that protect neurons against mitochondrial dysfunction and age-related neurodegeneration is limited. This project aims to address this knowledge gap and perform experiments to study a new mitochondrial quality control pathway for clearance of dysfunctional mitochondria and elucidate its role in neuroprotection against mitochondrial dysfunction and neurodegeneration. The proposed research is highly significant because the insights gained from this study will promote the discovery of new therapies to combat mitochondrial dysfunction and neurodegeneration in a variety of neurodegenerative diseases.

Genetic control of striatal NMDAR signaling for Parkinson’s disease therapy
Stella M. Papa, MD
Associate Professor
Yerkes National Primate Research Center
School of Medicine
Department of Neurology
Parkinson’s disease (PD) is characterized by motor abnormalities caused by loss ofmidbrain dopamine (DA) cells, which normally modulate the striatal neurons. DAdepletion is thus associated with abnormal function of the striatal projection neurons(SPNs). Our studies in animal models of PD and patients have revealed exaggeratedactivity of SPNs. One key contributor to pathological SPN activity is glutamate, and werecently demonstrated that blockade of glutamate receptors (NMDAR) in SPNs hasspecific motor effects. A strategy to reduce NMDAR transmission is to decrease theexpression of receptor subunits by silencing the genes, namely gene therapy. This canbe achieved locally injecting a virus to induce RNA expression that interferes specificallywith the target gene. Here, we propose an initial study to test the beneficial motor effectsof silencing the subunit GluN2B gene in the striatum for the treatment of PD symptoms.We will use the rat model produced by 6-hydroxydopamine lesion that expressesparkinsonian motor deficits and the abnormal involuntary movements (AIMs) induced byDA replacement with L-Dopa. Thus, this rat model also reproduces motor complicationsof chronic L-Dopa therapy. We will inject into the striatum of parkinsonian rats a virus tosilence the GluN2B gene or a nonspecific virus as control. Subsequently, we willcompare changes in parkinsonism and AIMs in correlation with GluN2B geneexpression. Data generated in this initial study will support continuation of work to furtherdevelop this gene therapy that may help restore full mobility in patients with PD.

Integrin affinity modulation in angiogenesis
Brian Petrich, PhD
Assistant Professor
School of Medicine
Department of Pediatrics
AFLAC Cancer and Blood Disorders Center
How and why blood vessel integrity is altered in pathological situations such as inflammatory disease or cancer are not well understood. We propose to examine how endothelial cell adhesion is regulated and to test how this process contributes to blood vessel function. We will investigate how particular proteins thought to be important for the adhesion of blood cells contribute to the adhesion and function of blood vessel function in adult mice. We have generated genetic mouse models in which we can specifically delete these proteins in endothelial cells of adult mice and study the results on blood vessel structure and function. Our initial results from these studies suggest that some of these adhesion regulatory proteins may play important roles in certain aspects of vascular function not previously appreciated. Results from our studies will lead to a better understanding of the fundamental processes that regulate cell adhesion and provide insights into the mechanisms that contribute to vascular dysfunction in the setting of inflammatory human disease.

 

 The GLFG nucleoporin, Nup98, and DNA Damage Repair
Maureen A. Powers, PhD
Associate Professor
School of Medicine
Department of Cell Biology
The maintenance of genome integrity, despite errors in DNA replication or damage from environmental factors, is crucial to guard against cancer progression.  Targeting tumor cells that have defects in DNA repair also provides a therapeutic approach to cancer.  Here we present biochemical and genetic data to support our hypothesis that a protein of the nuclear pore complex (nucleoporin) interacts with DNA damage-sensing factors to promote efficient DNA repair.  Importantly, we have previous shown this nucleoporin to have biophysical properties that uniquely enable its assembly into an aqueous gel. 
A new and exciting concept for organization of the nuclear interior suggests that certain proteins can associate into domains with aqueous gel-like properties.  We propose that the nucleoporin, Nup98, forms such a gel-like domain and, by also binding to factors that recognize DNA breaks, holds DNA ends together to facilitate repair.  In this proposal, we present two specific aims designed to generate additional supporting preliminary data needed for successful funding of an NIH proposal to study this process in depth.  We will determine 1) whether the physical properties that support gel formation by Nup98 are required for DNA repair, and 2) whether Nup98 can be found at sites of DNA damage.  The results of these aims should provide strong support for our NIH proposal and, importantly, for the functional significance and possible therapeutic potential of this newly identified mechanism of nuclear organization.

 

Galectin-9 is a Novel Regulator of Intestinal Homeostasis
Brian Robinson, MD, PhD
Instructor
School of Medicine
Department of Pathology
Inflammatory bowel diseases (IBDs), such as Crohn’s disease and ulcerative colitis, are a group of relapsing remitting conditions that affect the alimentary tract. They are characterized by a vicious cycle of epithelial damage, breakdown mucosal barrier, and subsequent uncontrolled inflammation. Despite significant research into the pathogenesis of IBD, the etiology of these disorders remains largely unknown and many patients are refractory to current therapeutics. This is due to the multifactorial nature of IBD pathogenesis, which includes contributions from genetics, diet, the environment, and the microbiome. Recent studies have implicated the galectin family of secreted lectins in the pathogenesis of IBD. Galectins have a high affinity for terminal galactoside carbohydrate structures that are enriched on the extracellular surface of cells. Defects in galectin expression and activity have been shown to result in critical defects in immune and epithelial cell function. Galectin-9 (Gal-9), in particular, has been linked to IBD through genome wide association studies. This proposal will investigate the mechanisms by which Gal-9 influences the maintenance and restitution of the epithelial barrier in the face of intestinal injury. We show that Gal-9-/- mice have marked defects in the face of multiple models of epithelial injury, and that ex vivo organoid cultures generated from Gal-9-/- mice have defects in culture. Moreover, we find that that Gal-9 can bind to bacteria in vitro and exert antimicrobial functions. Thus, Gal-9 appears that it may affect multiple drivers of IBD-pathogenesis, including epithelial restitution and microbial composition. In this proposal, we seek to define the nature of both of these interactions in vivo and thus detail a novel regulator of intestinal homeostasis.

 

Functional Diversity of NMDA Receptors in the Thalamus
Sharon A. Swanger, PhD
Instructor
School of Medicine
Department of Pharmacology
Communication  between  the  cerebral  cortex  and  thalamus  is  essential  for  integrating  sensations, movements, thoughts, and emotions, and altered communication between these brain structures results in pathological brain activity associated with epilepsy. The goal of this work is to determine if neuronal activity in the thalamus can be controlled by small molecules that modulate a subset of glutamate receptors. The cortex communicates with the thalamus through glutamatergic synaptic connections, but the specific glutamate receptors that mediate this communication remain unknown. The N-methyl-D-aspartate-type glutamate receptor (NMDAR) is critical for excitatory synapse function across the brain and has well-established roles in thalamic function and dysfunction. Since NMDARs are abundant in the brain, advancing NMDAR disease therapies requires finding a way to limit NMDAR modulation to select cell types or circuits. NMDAR diversity and recent advances in NMDAR pharmacology provide an opportunity to overcome this obstacle. We hypothesize that the four NMDAR subtypes (GluN2A-2D) expressed in the thalamus give rise to diverse NMDAR functions, which will allow GluN2-selective modulation to control activity at select synaptic connections. The proposed research utilizes novel GluN2-selective pharmacological tools with super-resolution microscopy and brain slice physiology to: 1) identify synapse-specific functions of NMDAR subtypes in the thalamus, and 2) define how NMDAR subtypes regulate thalamic excitation and inhibition. Completion of this research will address a critical knowledge gap by revealing mechanisms that regulate communication between the cortex and thalamus, and determine if GluN2-selective NMDAR modulation is a strategy for controlling neuronal function in the thalamus.

 

Brain-invading monocytes after status epilepticus
PI: Nicholas H. Varvel, PhD
Assistant Professor
School of Medicine
Department of Pharmacology
Status epilepticus is a frequent neurological emergency.  These unabated seizures reduce quality of life, promote the development of epilepsy, and can cause death.  Activation of microglia, the brain's resident immune cell, is an invariable feature of seizure activity.  However, the involvement of blood-borne immune cells in the brain's inflammatory reaction after seizures remains unresolved.  My preliminary studies have identified a blood cell type not normally encountered in the healthy brain, called a monocyte, which invades the brain tissue after seizures and contributes to inflammation.  Blocking brain entry of the blood monocytes was beneficial, reducing neuronal damage and accelerating weight regain. In this project, I will test if therapeutically targeting the monocytes after seizures leads to beneficial outcomes.  Then I will examine why brain-invading monocytes are pathogenic after brain injury. Success in this project would identify blood borne monocytes as a target to alleviate neuronal injury and neuroinflammation and protect against the development of co-morbidities caused by epilepsy.