2017 Rutgers BHI-RUN-NJIT Pilot Grants in Neuroscience have been awarded
We received 19 applications in response to the RFA. Each application was reviewed by two members of an external scientific review committee. The results of the scientific review were used by the internal programmatic review committee to select 8 applications for funding. The investigator teams that were funded included-
(1) Ronald Hart (RU-NB), Eliseo Eugenin (RBHS-NJMS), Peng Jiang (RU-NB) and Zhiping Pang (RBHS-RWJMS) (funded by BHI)
Interaction of opioids and HIV in developing human brain
Even with antiretroviral therapy, infection by Human Immunodeficiency Virus (HIV-1) persists in the population and is compounded by abuse of drugs including opioids. Drug abuse exacerbates effects of HIV infection to produce long-term deficits in working memory and neuropathology, defined as HIV-associated neurocognitive disorder (HAND). We propose to create human induced pluripotent stem cells (iPSC) lines from HIV-infected donors and differentiate them into neurons, astrocytes, microglia, and brain organoids for functional studies. We have previously studied iPSC carrying variants of the mu-opioid receptor (MOR; product of OPRM1 gene) and gene-edited versions of this gene. Astrocytic MOR expression is required for neurotoxicity but nothing is known about cell-specificity for activating latent viruses. We hypothesize that glial MOR mediates bystander toxicity on neurons and is the source of latent HIV for reactivation, both following opioid stimulation. The project will consist of two aims: (1) Obtain donor lymphocytes carrying latent HIV and reprogram them into iPSC. These will be tested for continued latency and capacity to produce infectious virus in neural cultures. (2) Use CRISPR/Cas9 gene editing to delete the OPRM1 gene in both HIV-1-infected iPSC and in uninfected iPSC for use as negative controls. We will also construct a lentivirus expressing regulated MOR as a replacement gene for use in the OPRM1-/- cells. Our long-term goal will be to establish a human brain microphysiological system to develop therapies for reducing the devastating consequences of NeuroAIDS and opioid abuse in HIV patients.
(2) Jorge Serrador (RBHS-NJMS) and Glenn Wylie (Kessler Institute) (funded by BHI)
The Efficacy of Dietary Nitrate Supplementation to Enhance Cognitive Function in Veterans Suffering with Gulf War Illness
Gulf War Illness (GWI) affects the lives of approximately 25-32% of military personnel who were deployed to the first Gulf War (1990). This multi-symptom condition is characterized by fatigue, headache, and sleep disturbances. Cognitive impairment is also a prevalent symptom which has a substantial impact on daily living of Veterans with GWI. Data collected in our lab have shown a reduced cerebrovascular function associated with GWI which may be accountable for the cognitive impairment in the GWI cohort. Additionally, important interventional studies have provided evidence of the efficacy of dietary nitrate supplementation, in the form of beetroot juice, to enhance cerebrovascular and cognitive function in healthy adults. It may be plausible for the benefits of this dietary supplementation of vegetable juice to be effective in the GWI population and potentially reduce the cognitive difficulties experienced by these Veterans. This collaborative project between the Department of Pharmacology, Physiology, and Neuroscience and the Kessler Foundation aims to provide preliminary data to explore the influence of dietary nitrate supplementation on cerebral hemodynamics and cognitive function in Veterans suffering with GWI. The investigators will use a range of magnetic resonance imaging and Doppler techniques to address the specific aims and collect the necessary data needed to apply for a larger Federal grant to study this potential therapeutic intervention further in both veterans with Gulf War Illness as well as other patient populations such as mild cognitive impairment.
(3) Gary Aston-Jones (BHI) and Nicholas Bello (RU-NB-SEBS) (funded by BHI)
The hypothalamic orexin system as a novel target for binge-eating pathology
Binge eating disorder (BED) is a major obstacle in the treatment of obesity, with 25-30% of obese individuals who seek medically-supervised weight loss having a diagnosis of BED. Unlike simple overeating, bingeing is accompanied by a sense of a “loss of control” over how much is eaten, characterized by a progressive escalation of intake of highly palatable food. In this way, many of the clinical characteristics of BED closely resemble symptoms of drug abuse disorders, pointing to possible commonalities in the neural circuitry underlying these disorders. The Aston-Jones laboratory was the first to identify a role for the hypothalamic orexin (hypocretin) system in drug reward and motivation, and subsequent studies have shown that compounds that block orexin signaling are highly effective at reducing drug seeking. In collaborative pilot studies between the Aston-Jones and Bello laboratories, we have shown using a novel behavioral economics paradigm that the orexin system underlies motivational changes that occur as a result of binge eating, specifically in obese animals. Here, we propose to investigate whether binge eating is associated with plasticity in orexin system function, as is the case following ‘binge’ cocaine use. We will also test the recently FDA-approved orexin receptor antagonist suvorexant as a pharmacological treatment to normalize motivation for food following binge eating in obese individuals. Thus, findings resulting from this application have direct translational outcomes for the treatment of BED. In addition, data generated here will form the basis of a collaborative NIH R01 application between PIs Aston -Jones and Bello in Feb 2019.
(4) Prabhas Moghe (RU-NB), Zhiping Pang (RBHS-RWJMS) and Jean Baum (RU-NB) (funded by BHI)
Nanotherapeutics for Aggregated Synuclein Protein Disorders in Parkinsons’ Disease
This proposal advances a transformative nanotherapy to a challenging problems in neuroscience and brain health namely, neurodegenerative diseases that arise from excessive protein aggregation in the brain. Alpha-synuclein (ASYN) is one of the disordered protein whose dysregulated degradation and clearance can lead to high levels of oligomers, which can be released and can cause neurotoxicity, a condition called synucleinopathies that occur in Parkinson’s disease (PD), multiple systems atrophy, and dementia with Lewy bodies (DLB). There are no satisfactory solutions to synucleinoapthies. This project develops a new vision for designing nanomaterial therapeutics for Parkinson’s disease and DLB. The hypothesis is to design synthetic nanoparticles based on scavenger receptor-binding amphiphilic macromolecules (AMs) that can target activated microglia, and rapidly de-escalate synuclein aggregation and counteract neurotoxicity in PD. In this project, two specific aims will be pursued collaboratively between Drs. Moghe (SoE-BME), Baum (SAS-Chemistry) and Pang (Neuroscience, RBHS): Aim 1: To design a new class of AM nanoparticles (NPs) to inhibit microglial-mediated intracellular ASYN oligomerization while enabling ASYN uptake and clearance under pathophysiologic conditions. Aim 2: To evaluate the ability of AM-based NPs to attenuate activation of the pro-inflammatory M1 microglial phenotype while enabling microglial ASYN clearance within a chronic neuroinflammatory environment in vivo. The outcomes of this project could advance a class of disease modifying therapeutic for PD and DLB and other ?-synucleinopathies, by blocking the inflammatory cycle of intracellular ASYN aggregation coupled with microglial activation.
(5) Radek Dobrowolski (RU-Newark) and Steven Levison (RBHS-NJMS) (funded by RU-Newark)
Proteotoxic Stress Pathways Induce Cell Death Following Brain Injury
Traumatic brain injury (TBI) is one of the most frequent causes of disability in the United States. TBI frequently leads to impairment of overall cognitive and motor functions; these permanent consequences are due to neuronal loss. Neuronal death is observed immediate and long after injury. TBI is characterized by a dysregulation of molecular clearance pathways, also known as the self-eating or autophagic pathways and buildup of abnormal proteins. Accumulation of these proteins within neurons is considered to be responsible for their progressive death. One major pathway triggered by neurotoxic proteins is the unfolded protein response (UPR), a pathway that is required to restore homeostasis but is also known to lead to cell death if stress is prolonged or too severe. We find that TBI-induced UPR is triggered by the inhibition of autophagy and that restoration of the autophagic function using specific membrane permeable peptides shortly after TBI is able to prevent apoptosis. Furthermore, our analyses identify the transcription factor EB (TFEB) to be the stress sensing factor responsible for UPR-induced neuronal death after TBI. Our preliminary data show a strong induction of TFEB following TBI, while a deletion of TFEB in the brain made neurons less susceptible to TBI-induced apoptosis. We propose to analyze the biochemical and cell biological mechanism of TFEB- mediated apoptosis after TBI using pharmacological and genetic approaches in vivo. Furthermore, we propose a potential therapeutic strategy using RNA interference based approach to transiently block expression of TFEB, abolish excessive UPR signaling and promote regeneration after TBI.
(6) Laszlo Zaborszky (RU-Newark) and Kasia Bieszczad (RU-NB-SAS) (funded by RU-Newark)
Circuit and molecular controllers on learning-induced auditory cortical plasticity
Acetylcholine (ACh) has long been known to be a critical component of learning, memory, attention, and cortical plasticity. However, how the underlying circuitry works to establish such functions remains unknown. Using monosynaptic viral tracing, the Zaborszky Lab have shown that cholinergic projection cells, including those that target the auditory cortex, receive a large proportion of their input from striatum (Chavez and Zaborszky, 2017). The role of the striatum in habit-learning and memory has been well established (Manns and Eichenbaum, 2008), however not in relation to the basal forebrain cholinergic (BFC) system. We propose using monosynaptic viral tracing with channelrhodopsin (ChR2) to target the specific circuit underlying learning induced plasticity in the primary auditory cortex (A1) in a behavioral paradigm developed by Dr. Bieszczad (Bieszczad and Weinberger, 2012). We hypothesize that 1) early in learning, A1 plasticity is induced by a cholinergic influence dominated by BFC and 2) late-stage habit learning which leads to a reduction A1 cortical cue representation mediated by a gradual increase in striatal inhibitory influence on BFC function. We propose to use electrophysiological recordings to monitor the temporal dynamics between the striatum-BFC-A1 circuitry and to test the hypothesized inhibitory role of the striatum in this circuit via optogenetic stimulation during learning, to block cortical plasticity. Further, we will relate these changes in behavior and neuroplasticity to changes in molecular level markers, including immediate early genes and gene candidates encoding subunits for cholinergic receptors in order to understand the neurobiological basis of auditory memory strength and behavioral flexibility.
(7) William Graves (RU-Newark) (funded by RU-Newark)
Using brain perfusion changes during stroke recovery to predict reading recovery
Strokes in the left hemisphere are well known to lead to problems with spoken language, a condition known as aphasia. Less widely appreciated is the fact that survivors of left hemisphere stroke may also be left with impairments in their ability to read. Such impairments can have a major negative impact on quality of life, ranging from loss of reading as a leisure activity to problems returning to work. If we are to help these survivors, we need to know about the timing of reading recovery following stroke, and the areas of the brain in which these changes most critically occur. To accomplish this, we will measure changes in brain perfusion (blood flow) from the subacute (2-5 weeks) to chronic (3 months or greater) epochs following stroke. This will be done using a brain imaging technique known as Arterial Spin Labeling, a non-invasive technique for measuring both brain activation and blood flow. The current lack of detailed understanding of the neural and behavioral course of reading recovery following stroke is a major obstacle for improving therapies that promote reading recovery. The goal of this project is to better characterize the time course and neural substrates of reading recovery following stroke. Such knowledge will help better define the prognosis of recovery and plan more effective treatments. It may also form the foundation for developing additional therapies such as behavioral interventions or noninvasive brain stimulation.
(8) Xiaoyang Xu (NJIT) and Peng Jiang (RU-NB-SAS) (funded by NJIT)
Injectable amino acid containing hydrogel with photoluminescent property for stem cell-based repair of injured spinal cord
Developing effective treatments for spinal cord injury (SCI) remains a daunting challenge for scientists and academic clinicians. It has been increasingly recognized that SCI is not a monolithic entity but rather a complex of concurrent, interlocked and interacting pathological events. Human neural stem cells (hNSCs) have the capacity to proliferate, migrate and differentiate into oligodendrocytes, astrocytes and neurons of the central nervous system (CNS). However, developing hNSC transplantation therapies has been jeopardized by the poor survival of donor cells, therapeutic function and neural lineage differentiation in lesioned spinal cord due to its inhibitory environment to regenerative mechanisms. Encouragingly, injectable hydrogels have newly emerged as a powerful chemical engineering strategy for cell delivery. They offer minimally invasive, localized, cavity-filling and biodegradable scaffolding features for carrying hNSCs to the injury epicenter to improve their survival and overall therapeutic impacts. Furthermore, fluorescent hydrogels signify a highly desirable technology for intra-spinal cord hNSC implantation that can be readily tracked by fluorescent imaging to chronically monitor donor cell distribution and hydrogel degradation. This proposed research aims to develop a novel injectable, tissue compatible and biodegradable hydrogel platform with photoluminescent and antioxidant-releasing properties for minimally invasive transplantation of hNSCs to augment its SCI repair efficacy via imaging-based implant optimization. We believe the proposed multimodal strategy that integrates injectable scaffolding, hNSC, bioimaging and drug delivery, will ultimately augment hNSC-based acute spinal cord repair and mitigate debilitating complications for people living with traumatic SCI conditions.