2000 — 2003 |
Lu, Hui-Chen |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Adenylyl Cyclase in Barrel Cortex Development @ Baylor College of Medicine
adenylate cyclase; developmental neurobiology; thalamocortical tract; vibrissae; electrophysiology; synapses; neural plasticity; genetically modified animals; laboratory mouse;
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1 |
2005 — 2008 |
Lu, Hui-Chen |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Camp Signaling Cascades in Sensory Map Development @ Baylor College of Medicine
DESCRIPTION (provided by applicant): In cortical sensory maps, thalamocortical afferents (TCAs) transmit peripheral sensations in organized arrays into distinct neuronal modules to provide a topographic representation of the external sensory world. The specialized release features of mature TCAs allow efficient synaptic transmission and rapid adaptation to repetitive stimuli. If this pathway is dysfunctional, the brain cannot interpret sensory cues. Yet, the mechanisms underlying the development of the cortical map and the functional properties of this pathway is largely unknown. In barrelless mice, a loss-of-function mutant of calcium/calmodulin-activated adenylyl cyclase 1 (AC1), TCAs reach their cortical target but fail to form a barrel map, the mouse somatosensory map. In addition, TCAs do not mature properly in barrelless mice, which suggests that AC1-mediated signaling pathways are required not only for establishing the correct architecture of the TCAs but also for the functional development of the TCA itself. Interestingly, the functional maturation of the TCA release machinery occurs concurrently with the formation of the barrel map. It has been shown that AC1 mediates long-term synaptic enhancement and is required for learning and memory. We hypothesize that the naturally occurring synaptic enhancement mediated by AC1 during cortical map formation utilize the same mechanisms underlying presynaptic-origin synaptic plasticity. Further, we posit that AC1 modulates the functional interactions among synaptic vesicle proteins and active zone proteins to facilitate neurotransmitter release. A combination of electrophysiological, pharmacological, anatomical, and biochemical techniques will be employed to compare the functional, structural, and biochemical properties of wild type and barrelless TCAs. The role of the putative AC1 targets RIM and Synapsin (identified in this project) during sensory map formation will be studied by examining barrel map formation in their loss-of-function mutant mice. For the first time we will be able to correlate cortical map development with sensory function at a molecular level.
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2010 — 2011 |
Lu, Hui-Chen Mackie, Kenneth P. [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Do Organophosphates Impair Neurodevelopment Through Inhibition of Endocannabinoid @ Indiana University Bloomington
DESCRIPTION (provided by applicant): This is a NIDA CEBRA R21 application to determine if the deleterious effects of organophosphates on neurodevelopment are due to inhibition of endocannabinoid degradation. Organophosphates are effective and widely used pesticides that have improved human health and crop yields. However, one concerning chronic toxicity of organophosphates is their deleterious effect on neurodevelopment, which can occur independent of acetylcholinesterase (AChE) inhibition. In addition to AChE, organophosphates inhibit other esterases, including fatty acid amino hydrolase (FAAH) and monoacylglycerol lipase (MGL). FAAH and MGL are the two most important enzymes for the degradation of endocannabinoids. Significantly, inhibition of FAAH and MGL occurs at organophosphate concentrations that can be achieved in vivo. How might organophosphates perturb neurodevelopment? Emerging evidence has established that the endocannabinoid system plays a central role in brain development including in the proliferation of neural progenitors, neuronal migration and neural circuit formation. We have found that pharmacological blockade of endocannabinoid signaling and degradation disrupts these processes. In the proposed work we will complete two specific aims to determine if organophosphate inhibition of endocannabinoid degradation leads to abnormalities in neurodevelopment and later behavior: Aim 1. Does perinatal organophosphate exposure inhibits eCB degradation in the developing brain to cause abnormal neurodevelopment? Aim 2. Will perinatal organophosphate treatment produce behavioral changes in adult animals? If so, are these changes mediated by CB1 signaling during development? Successful completion of these aims will enable us to determine if inhibition of eCB degradation and enhanced cannabinoid receptor signaling underlie the adverse neurodevelopmental effects of organophosphates. Furthermore they will help us understand the role of FAAH and MGL in orchestrating the complex task of assembling the nervous system. Finally, they will tell us if perturbation of MGL and FAAH function during development predisposes to later behavioral abnormalities and susceptibility to drug use. PUBLIC HEALTH RELEVANCE: Commonly used organophosphate pesticides can cause abnormalities in nervous system development. This proposal will test the hypothesis that organophosphate pesticides impair degradation of endogenous cannabinoids in the fetal and newborn brain and that this leads to anatomical and behavioral deficits in later life. The results of this study could have significant public health benefits for children exposed in utero to organophosphate pesticides.
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0.904 |
2010 — 2011 |
Lu, Hui-Chen Mackie, Kenneth P. [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Will Therapeutic Dosing of Fatty Acid Amino Hydrolase Inhibitors Disrupt Neuronal @ Indiana University Bloomington
DESCRIPTION (provided by applicant): This is an R21 application in response to PAR-08-216, "Developmental Pharmacology". Inhibitors that slow the degradation of the endocannabinoid anandamide show great promise for treating anxiety, depression, and pain, and are in clinical trials for the latter two indications. These inhibitors increase anandamide levels by blocking its hydrolysis by fatty acid amide hydrolase (FAAH) leading to enhanced endocannabinoid signaling, primarily through CB1 cannabinoid receptors. The acute side effects of FAAH inhibitors are well delineated and relatively mild. However, FAAH inhibitors are being developed for chronic use and the long-term effects of these drugs, particularly on the brain as it develops, are poorly studied and not well understood. Endocannabinoids such as anandamide play key roles in numerous physiological processes throughout the body. One of these processes is neurodevelopment where endocannabinoids modulate neurogenesis, neuronal migration, and axonal pathfinding. Genetic or pharmacological disruption of endocannabinoid signaling during neurodevelopment alters CNS development. The proposed studies will use mice and a multidisciplinary approach to determine if therapeutically active doses of FAAH inhibitors raise embryonic brain levels of anandamide and related N-acyl amides to levels sufficient to impair neurodevelopment and later CNS function (behavior and neuronal excitability) by addressing two specific aims: Aim 1. Will therapeutic dosing of FAAH inhibitors suppress embryonic brain FAAH activity leading to abnormal neurodevelopment? We will use mass spectrometry to determine if therapeutic doses of FAAH inhibitors increase anandamide and related N-acyl amides in developing brain. We will then determine if these FAAH inhibitors affect neurogenesis, neuronal migration, or axonal pathfinding. The involvement of cannabinoid receptors in these processes will be evaluated using pharmacological or knockout approaches. Aim 2. Will therapeutic dosing of FAAH inhibitors during the perinatal period lead to sustained impairment of behavior and synaptic function/plasticity during adulthood? Mice will be treated through the perinatal period with FAAH inhibitors identified in the first specific aim. These mice will then undergo behavioral testing as adults in a gender-specific fashion for anxiety, drug preference, spatial learning, and fear conditioning. In addition we will examine synaptic plasticity and excitation/inhibition balance during adulthood. By completing these two aims we will gain insight into the neurodevelopmental effects of FAAH blockade and will be provided with valuable data on the potential consequences of FAAH inhibition during pregnancy. PUBLIC HEALTH RELEVANCE: Inhibitors of the breakdown of the endogenous cannabinoid, anandamide, are undergoing clinical trials for pain and depression. We have found that perturbation of endocannabinoid signaling, including inhibition of anandamide breakdown, leads to derangements in neurodevelopment. In the proposed work we will determine if therapeutic doses of anandamide degradation inhibitors detrimentally affect neurodevelopment.
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0.904 |
2011 — 2015 |
Lu, Hui-Chen |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Signaling Cascades in Sensory Map Development @ Baylor College of Medicine
DESCRIPTION (provided by applicant): In cortical sensory maps, thalamocortical afferents (TCAs) transmit peripheral sensations in organized arrays into distinct cortical neuronal modules to provide a topographic representation of the external sensory world. These cortical maps that form in every individual can be altered by exposure to abnormal sensory experience during a critical period of postnatal development. Mis-wiring of neuronal circuits during early life is likely to be a major cause of neurological disorders, including autism, schizophrenia, and congenital epilepsy. Using mouse whisker-maps as a model system, we found that metabotropic glutamate receptor 5 (mGluR5) signaling is involved in sculpting the anatomical structures and in regulating synaptic function and plasticity of thalamocortical connections. Eliminating mGluR5 function in cortical principal neurons resulted in a prolonged critical period for lesion-induced rearrangements of TCAs. Endocannabinoids (eCBs), known retrograde messengers in regulating synaptic transmission, are synthesized upon mGluR5 activation in many neurons. We hypothesize that during cortical map development mGluR5 signaling in cortical neurons instructs the anatomical modification of TCAs and that eCBs mediate, at least in part, the neural-activity dependent remodeling of thalamocortical synapses. In the proposed work we will address three specific aims: How does mGluR5 affect the development and plasticity of barrel cortex? How does mGluR5 affect functional development of cortical circuits and network activity? Do endocannabinoids mediate mGluR5 influences on developing cortical circuits? A combination of genetic, anatomical, electrophysiological, and pharmacological approaches will be employed to accomplish these aims. This study will provide a firm understanding of mGluR5 and eCBs signaling in developing neural circuits. Both mGluR5 and eCBs are potential drug targets for therapeutic interventions in humans. A detailed knowledge of their roles during neural development is critical not only for understanding normal brain function, but also to provide significant insights for the rational assessment of therapies or drug exposure (e.g., cannabis) that might affect the developing fetus.
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2014 — 2019 |
Lu, Hui-Chen |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Molecular and Genetic Studies of Nmnat2 in Neuroprotection @ Indiana University Bloomington
DESCRIPTION (provided by applicant): Proper brain function requires an active maintenance program to sustain neuronal health. In essence, neurons and glia have to repair the damage that is induced by neuronal activity, injury, toxins, and aging. Environmental stressors impact the nervous system and lead to neuronal dysfunction and degeneration if the protective mechanisms are weakened. Recent studies revealed that NMNATs (nicotinamide mononucleotide adenylyl transferase) maintain neuronal integrity and facilitate proper neural function throughout life. NMNAT2 is the major NMNAT isoform expressed in the mammalian brain and is extremely labile with a short half-life in neurons. We and others have found that NMNAT2 levels are significantly reduced in CNS tissues from patients with Alzheimer's disease, tauopathies, or Parkinson's disease. Reducing NMNAT2 function in mice leads to axonal deterioration, while NMNAT2 overexpression offers neuroprotection. In the proposed work we will address three specific aims: How does NMNAT2 reduce toxic tau species and protect neurons against tauopathy? Is NMNAT2 required to maintain neuronal health in adult brains? Is small molecule up-regulation of NMNAT2 levels neuroprotective? A combination of molecular/biochemical, genetic, anatomical, electrophysiological, imaging, viral vector and high-throughput screening approaches will be employed to accomplish these aims. This study will provide insight into how NMNAT2 maintains neuronal health in mature brains. NMNATs are potential drug targets for therapeutic interventions in neurodegeneration. A detailed knowledge on how NMNAT2 maintain neuronal integrity and its role in neuroprotection is critical not only for understanding normal brain function, but will also provide necessary insights to assist in drug discovery.
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