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Principal Investigator: Mostafa Zamanian
Organization: UNIVERSITY OF WISCONSIN-MADISON
Fiscal Year: 2024
Award: $383,923
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Parasitic nematodes infect over 1.5 billion humans. Control of this poverty-associated global health burden relies
almost entirely on the administration of a small number of anthelmintic drugs. The prospects of anthelmintic
resistance and the sub-optimal nature of these drugs in many nematode parasites demand new approaches to
parasite treatment and control. However, the need to develop new antiparasitic treatment options is hampered
by large gaps in our basic knowledge of the nematode biological processes that promote the establishment and
maintenance of infection. Excretory-secretory (ES) products released by parasitic nematodes into their host
environments are essential for host immune modulation and successful parasitism. Despite the general under-
standing that the ES system is a conduit for the release of molecules (proteins and vesicles) that promote parasite
survival, we have a poor understanding of the underlying structure and function of the ES apparatus in medically
important parasitic nematodes. To address this gap in knowledge, this project will identify regulators of secretory
function in Brugia malayi, a mosquito-transmitted filarial nematode and causative agent of human lymphatic filar-
iasis (LF). Recent studies in B. malayi, including on the mode of action of ivermectin, support the premise that
the ES apparatus is a lucrative and unexploited source of new therapeutic targets. Our overarching hypothesis
is that cell-surface receptors localized to the B. malayi ES system directly or indirectly control parasite secretory
function, and that they can be targeted to interfere with the release of ES-derived molecules. We will pursue
three aims, motivated by preliminary receptor leads and made feasible by innovative methods we have optimized
to resolve the transcriptomic state of the B.malayi ES system and to profile receptors implicated in parasite se-
cretory function. We focus our efforts on G protein-coupled receptors (GPCRs), which are prolific drug targets
and known to be expressed in nematode ES cells and adjacent cell types that may act on the ES system. In
Aim 1, we will use innovative spatial transcriptomics approaches to resolve the transcriptome of the B. malayi
ES region across intra-host stages and to identify candidate GPCRs that regulate ES function. In Aim 2, we will
use reverse genetics and chemical approaches to assess the role of ES-localized GPCRs in the regulation of
B. malayi secretory function. In Aim 3, we will use whole-organism model nematode and mammalian single-cell
heterologous expression platforms to define the pharmacology of ES-localized GPCRs and to establish functional
assays for GPCR screening. Completion of this project will produce fundamental new knowledge about the filarial
nematode ES system and deliver new lead targets and validated screens for novel anti-filarial drug discovery.
Terms: <21+ years old><Address><Adult><Adult Human><Anthelmintics><Antihelminthic Agent><Antihelminthic Drugs><Antiparasitic Agents><Antiparasitic Drugs><Antiparasitics><Assay><Bancroftian Elephantiasis><Bio-Informatics><Bioassay><Bioinformatics><Biological Assay><Biological Function><Biological Process><Biological Symbiosis><Body Tissues><Brugia><Brugia malayi><C elegans><C. elegans><C.elegans><Caenorhabditis elegans><Cell Body><Cell Surface Receptors><Cells><Chemicals><Chronic disability><Communication><Culicidae><Data><Development><Diagnostic><Drug Targeting><Drugs><Environment><Excretory function><Filarial Elephantiases><Filariasis><Filarioidea Infections><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><Goals><Health><Helminths><High Throughput Assay><Human><Immune><Immunes><Immunomodulation><Impoverished><Infection><Ivermectin><Knowledge><Larva><Lead><Life Cycle><Life Cycle Stages><Ligands><Lymphatic><Lymphatic Filariasis><Maintenance><Mammalian Cell><Measures><Medical><Medication><Medicine><Methods><Mining><Modern Man><Molecular><Mosquitoes><Nature><Nematoda><Nematode infections><Nematodes><Parasite Control><Parasites><Parasitic Diseases><Parasitic Worms><Parasitic nematode><Parasiticides><Pb element><Persistent disability><Persons><Pharmaceutical Preparations><Pharmacology><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Poverty><Process><Protein Secretion><Proteins><RNA Interference><RNA Silencing><RNAi><Receptor Activation><Receptor Protein><Regulation><Research><Resistance><Role><Secretory Cell><Sequence-Specific Posttranscriptional Gene Silencing><Source><Structure><System><Tissue Model><Tissues><Transmission><Vaccines><Vermifuges><Vesicle><Whole Organism><adulthood><antihelminthic><candidate identification><cell type><developmental><disease control><disorder control><drug discovery><drug/agent><excretion><exosome><filarial disease><filarial infection><global gene expression><global health><global transcription profile><heavy metal Pb><heavy metal lead><high throughput screening><immune modulation><immune regulation><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><in vitro Assay><innovate><innovation><innovative><interest><life course><loss of function><model organism><new approaches><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel approaches><novel drug target><novel druggable target><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic target><novel therapy target><parasitic roundworm><parasitism><pathogen><pharmacologic><prevent><preventing><programs><receptor><resistant><response><reverse genetics><roundworm><roundworm infection><screening><screenings><social role><spatiotemporal><success><transcriptome><transcriptomics><transmission process>