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Principal Investigator: Maegan M Weltzin
Organization: UNIVERSITY OF ALASKA FAIRBANKS
Fiscal Year: 2024
Award: $77,500
Funding agency: National Institute of Mental Health
ABSTRACT. In the U.S., major depressive disorder (MDD) is the most common mental disorder,
with depression prevalence approaching 20% among adolescents and young adults. Current
pharmacological treatments are unsatisfactory in that 33-55% of people suffering from MDD are
non-responsive. MDD is associated with alterations in neurotransmitter systems including
hypercholinergic tone modulated by nicotinic acetylcholine receptors (nAChRs) and decreased
brain-derived neurotrophic factor (BDNF) expression. nAChRs are abundant in the central
nervous system, and hypercholinergic tone, in part caused by α7-nAChR activation, is associated
with depression. Pharmacologically desensitizing α7-nAChRs improves depressive symptoms in
mice. Common serotonin and norepinephrine reuptake inhibitor therapies antagonize nAChRs
non-selectivity (off target effect) and enhance BDNF levels at clinically effective doses. Excitingly,
reducing expression of programmed cell death 4 (Pdcd4) protein, a translation inhibitor, by small
interfering RNA (siRNA) delivered by a cell penetrating peptide (CPP), enhances BDNF
expression to reverse depressive-like behaviors in mice. However, caution must be taken as
CPPs interact broadly with cellular macromolecules and lipid bilayers resulting in uncontrolled
cargo delivery. To begin to combat this issue, we developed an α7-nAChR selective CPP. Our
preliminary data show that the lead CPP is not cytotoxic and can transport a fluorophore into
neuronal-like cells by an α7-nAChR dependent mechanism. These underlying findings led us to
our hypothesis that the novel lead CPP, a selective α7-nAChR antagonist, coupled with Pdcd4
siRNA may be able to achieve our important goal to help those suffering from MDD. Defining if
the lead CPP can move siRNA cargo into cells and mammalian brain will remove critical barriers
that stymie scientific and clinical MDD work, in addition to other conditions affected by α7-nAChR
dysregulation. We will pursue the aims of this proposal by comparing cell culture and in vivo
application of the lead CPP complexed with fluorophore-tagged siRNA to determine if the siRNA
can be delivered to cause a cellular effect. We will combine live-cell confocal microscopy, brain
imaging, western blot, and ELISA assays. Anticipated outcomes may also reveal potential utility
of the lead CPP as a research tool. Application funding will provide foundational support for PI
Weltzin’s progress towards becoming an independent researcher by demonstrating project
feasibility, assay advancement, preliminary data generation, and a senior-author publication.
Terms: <5-HT><5-Hydroxytryptamine><5HT><Acceleration><Address><Adolescent and Young Adult><Affect><Alpha Cell><Apoptosis><Apoptosis Pathway><Assay><BBB crossing><BDNF><Behavior><Bioassay><Biological Assay><Body Tissues><Brain><Brain Nervous System><Brain imaging><Brain-Derived Neurotrophic Factor><CNS Nervous System><Cell Body><Cell Culture Techniques><Cell Line><CellLine><Cells><Central Nervous System><Clinical><Complex><Confocal Microscopy><Coupled><Cultured Cells><Data><Development><Development and Research><Dose><Drugs><ELISA><Embryo><Embryonic><Emotional Depression><Encephalon><Enteramine><Enzyme-Linked Immunosorbent Assay><Epilepsy><Epileptic Seizures><Epileptics><Feasibility Studies><Female><First Generation College Students><First Generation College graduates><First Generation Students><Fluorescein><Funding><Future><Generations><Glucagon Cell><Glucagon Secreting Cell><Goals><Harvest><Health><Hippophaine><Hispanic Populations><Hispanic group><Hispanic individual><Hispanic people><Hispanics><Human><Image><Immunoblotting><Individual><Injections><Investigators><Ion Channel Gating><Ion Channel Gatings><Kidney><Kidney Urinary System><Knowledge><Laboratories><Lead><Levarterenol><Levonorepinephrine><Ligands><Lipid Bilayers><Location><Major Depressive Disorder><Medication><Mental Depression><Mental disorders><Mental health disorders><Mice><Mice Mammals><Mission><Modern Man><Murine><Mus><NIH><NIMH><National Institute of Mental Health><National Institutes of Health><Native Americans><Nerve Cells><Nerve Transmitter Substances><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neuraxis><Neuroblastoma><Neurocyte><Neurologic Disorders><Neurological Disorders><Neurons><Neurotransmitters><Nicotine Dependence><Nicotinic Acetylcholine Receptors><Nicotinic Receptors><Noradrenaline><Norepinephrine><Organ><Outcome><Pb element><Penetration><Peptides><Peripheral><Peripheral Nervous System><Persons><Pharmaceutical Preparations><Pharmacological Treatment><Pilot Projects><Position><Positioning Attribute><Prevalence><Process><Production><Programmed Cell Death><Proteins><Psyche structure><Psychiatric Disease><Psychiatric Disorder><Publications><R & D><R&D><RNA Degradation><Research><Research Methodology><Research Methods><Research Personnel><Research Support><Researchers><Science><Scientific Publication><Seizure Disorder><Serotonin><Short interfering RNA><Small Interfering RNA><Strains Cell Lines><Strategic Planning><System><Technology><Therapeutic><Time><Tissues><Translations><Underrepresented Groups><Underrepresented Populations><Underrepresented Students><United States National Institutes of Health><Western Blotting><Western Immunoblotting><Work><alpha-bungarotoxin binding sites><alpha-bungarotoxin receptor><alpha-cell><alpha7 nicotinic acetylcholine receptor><alpha7nAChR><antagonism><antagonist><blood-brain barrier crossing><bloodbrain barrier crossing><brain tissue><brain visualization><burden of disease><burden of illness><cell culture><cell cultures><cholinergic><clinical depression><combat><cultured cell line><deliver short interfering RNA><deliver siRNA><deliver small interfering RNA><delivery system for siRNA><delivery system for small interfering RNA><delivery vectors for siRNA><depression><depression symptom><depressive><depressive symptoms><desensitization><design><designing><developmental><disease burden><drug development><drug discovery><drug/agent><enzyme linked immunoassay><epilepsia><epileptogenic><experience><fluorophore><graduate student><hands on research><heavy metal Pb><heavy metal lead><imaging><improved><in vivo><inhibitor><inhibitor drug><inhibitor therapeutic><inhibitor therapy><lipid bilayer membrane><macromolecule><major depression><major depression disorder><member><mental><mental illness><nano particle><nano-sized particle><nanoparticle><nanosized particle><neurological disease><neuronal><nicotine addiction><nicotine dependent><novel><pharmacologic><pilot study><protein blotting><protein expression><psychiatric illness><psychological disorder><renal><research and development><research and methods><reuptake><short interfering RNA delivery><siRNA><siRNA delivery><side effect><small interfering RNA delivery><success><timeline><tool><translation><treatment strategy><under representation of groups><under represented groups><under represented people><under represented populations><underrepresentation of groups><underrepresented people><α-cell><α7 nicotinic acetylcholine receptor><α7nAChR>