Biology subjects

Park, A. Y.

Publications and source records attributed to Park, A. Y..

5 recordsLinked to original sources

bioRxiv2026

Immunoregulatory gene GIMAP6 suppresses lethal atherosclerotic vasculopathy and ischemic heart failure

Controlling hyperlipidemia has reduced but not eliminated atherosclerotic cardiovascular disease as a predominant cause of human mortality. Here, we report that loss of the immunoregulatory gene GTPase of immunity-associated protein 6 (GIMAP6), causes an inflammatory vasculopathy and accelerated atherosclerosis in the absence of hyperlipidemia. These pathologic changes in turn result in progressive cardiac ischemia, myocardial infarction, and heart failure, culminating in early death. In humans, rare deleterious GIMAP6 variants are associated with premature severe cardiovascular disease. These findings reveal GIMAP6 to play an important protective role against atherosclerotic cardiovascular disease whose identification offers opportunities for improved risk management and a target for new therapies.

immunology↗

bioRxiv2024

Control of OPC proliferation and repopulation by the intellectual disability gene PAK1 under homeostatic and demyelinating conditions

Appropriate proliferation and repopulation of oligodendrocyte progenitor cells (OPCs) determine successful (re)myelination in homeostatic and demyelinating brains. Activating mutations in p21-activated kinase 1 (PAK1) cause intellectual disability, neurodevelopmental abnormality, and white matter anomaly in children. It remains unclear if and how PAK1 regulates oligodendroglial development. Here, we report that PAK1 controls proliferation and regeneration of OPCs. Unlike differentiating oligodendrocytes, OPCs display high PAK1 activity which maintains them in a proliferative state by modulating PDGFRa-mediated mitogenic signaling. PAK1-deficient or kinase-inhibited OPCs reduce their proliferation capacity and population expansion. Mice carrying OPC-specific PAK1 deletion or kinase inhibition are populated with fewer OPCs in the homeostatic and demyelinated CNS than control mice. Together, our findings suggest that kinase-activating PAK1 mutations stall OPCs in a progenitor state, impacting timely oligodendroglial differentiation in the CNS of affected children and that PAK1 is a potential molecular target for replenishing OPCs in demyelinating lesions.

neuroscience↗

bioRxiv2023

Using Unstructured Crowd-sourced Data to Evaluate Urban Tolerance of Terrestrial Native Species within a California Mega-City

In response to biodiversity loss and biotic community homogenization in urbanized landscapes, City managers around the world are increasingly working to conserve and increase urban biodiversity. Accordingly, around the world, previously extirpated species are (re)colonizing and otherwise infiltrating urban landscapes, while once abundant species are in various states of decline. Tracking the occurrence of traditionally urban intolerant species and loss of traditionally urban tolerant species should be a management goal of urban areas, but we generally lack tools to study this phenomenon. To address this, we first used species occurrences from iNaturalist, a large collaborative dataset of species observations, to measure an urban association index (UAI) for 967 native animal species that occur in the city of Los Angeles. On average, the occurrence of native species was negatively associated with our composite measure of urban intensity, with the exception of snails and slugs, which instead occur more frequently in areas of increased urban intensity. Next, we assessed 8,348 0.25 x 0.25 mile grids across the City of Los Angeles to determine the average grid-level UAI scores (i.e., a summary of the UAIs present in a grid cell, which we term Community Urban Tolerance Index or CUTI). We found that areas of higher urban intensity host more urban tolerant species, but also that taxonomic groups differ in their aggregate tolerance of urban areas, and that spatial patterns of tolerance vary between groups (e.g., mammals are not the same as birds). The framework established here was designed to be iteratively reevaluated by city managers of Los Angeles in order to track the progress of initiatives to preserve and encourage urban biodiversity, but can be rescaled to sample different regions within the city or different cities altogether to provide a valuable tool for city managers globally.

ecology↗

bioRxiv2023

Follicle stimulating hormone signaling opposes the DRL-1/FLR-4 MAP Kinases to balance p38-mediated growth and lipid homeostasis in C. elegans

Animals integrate developmental and nutritional signals before committing crucial resources to growth and reproduction; however, the pathways that perceive and respond to these inputs remain poorly understood. Here, we demonstrate that DRL-1 and FLR-4, which share similarity with mammalian mitogen-activated protein kinases, maintain lipid homeostasis in the C. elegans intestine. DRL-1 and FLR-4 function in a protein complex at the plasma membrane to promote development, as mutations in drl-1 or flr-4 confer slow growth, small body size, and impaired lipid homeostasis. To identify factors that oppose DRL-1/FLR-4, we performed a forward genetic screen for suppressors of the drl-1 mutant phenotypes and identified mutations in flr-2 and fshr-1, which encode the orthologues of follicle stimulating hormone and its putative G protein-coupled receptor, respectively. In the absence of DRL-1/FLR-4, neuronal FLR-2 acts through intestinal FSHR-1 and Protein Kinase A signaling to restrict growth. Furthermore, we show that opposing signaling through DRL-1 and FLR-2 coordinates TIR-1 phase transition, which modulates downstream p38/PMK-1 activity, lipid homeostasis, and development. Finally, we identify a surprising noncanonical role for the developmental transcription factor PHA-4/FOXA in the intestine where it restricts growth in response to impaired DRL-1 signaling. Our work uncovers a complex multi-tissue signaling network that converges on p38 signaling to maintain homeostasis during development.

developmental biology↗

bioRxiv2021

Human immunodeficiency reveals GIMAP5 as lymphocyte-specific regulator of senescence

Elucidating the molecular basis of immunodeficiency diseases is a powerful approach to discovering new immunoregulatory pathways in humans. Here we report 10 affected individuals from 4 families with a new immunodeficiency disease comprising of severe progressive lymphopenia, autoimmunity, immunodeficiency, and liver disease due to recessive loss of function variants in "GTPase of immunity-associated proteins" protein 5 (GIMAP5). We show that the disease involves the progressive loss of naive T lymphocytes and a corresponding increase in antigen-experienced, but poorly functional and replicatively senescent T cells. In vivo treatment of Gimap5-deficient mice with rapamycin (an inhibitor of mTORC1) significantly restores the fraction of naive T lymphocytes. Furthermore, a GIMAP5-deficient human patient who was treated with rapamycin (sirolimus) showed a remarkable reduction in spleen/lymph node size. Together, these observations reveal that GIMAP5 plays a critical role in lymphocyte metabolism which is essential for senescence prevention and immune competence, suggesting that an inhibitor of mTORC1 could be a valuable clinical intervention in treating patients deficient for GIMAP5.

immunology↗