A5022786763- Barrier Structure and Function Studies
- Cervical Cancer and HPV Research
- Reproductive tract infections research
- Angiogenesis and VEGF in Cancer
- Neuroinflammation and Neurodegeneration Mechanisms
- Cellular transport and secretion
- Calcium signaling and nucleotide metabolism
- Retinal Development and Disorders
- Single-cell and spatial transcriptomics
- Pelvic floor disorders treatments
- Reproductive System and Pregnancy
- Parkinson's Disease Mechanisms and Treatments
- Lysosomal Storage Disorders Research
- Cell Adhesion Molecules Research
- Hippo pathway signaling and YAP/TAZ
- Extracellular vesicles in disease
- Caveolin-1 and cellular processes
- Synthesis and biological activity
- Mosquito-borne diseases and control
- Autophagy in Disease and Therapy
- Protein Structure and Dynamics
- Photoacoustic and Ultrasonic Imaging
- Cancer-related molecular mechanisms research
- Adenosine and Purinergic Signaling
- Axon Guidance and Neuronal Signaling
Harvard University
2023-2025
Columbia University
2024-2025
Columbia University Irving Medical Center
2017-2024
Harvard University Press
2024
Inspire
2024
Gates Foundation
2024
Defects in endolysosomal and autophagic functions are increasingly viewed as key pathological features of neurodegenerative disorders. A master regulator these is phosphatidylinositol-3-phosphate (PI3P), a phospholipid synthesized primarily by class III PI 3-kinase Vps34. Here we report that disruption neuronal Vps34 function vitro vivo impairs autophagy, lysosomal degradation well lipid metabolism, causing membrane damage. PI3P deficiency also promotes secretion unique exosomes enriched for...
Significance Membranes can adopt distinct phases. The endoplasmic reticulum (ER) is the largest membrane system inside cells and also harbors richest metabolic activity including lipid synthesis. Unlike plasma where separated “lipid raft” domains have been predicted observed, ER thought to be uniformly fluidic. However, such understanding based on biophysical studies of model under thermodynamic equilibrium. It remains unclear whether how synthesis perturbs equilibrium promotes phase...
Enteric symptoms are hallmarks of prodromal Parkinson's disease (PD) that appear decades before the onset motor and diagnosis. PD patients possess circulating T cells recognize specific α-synuclein (α-syn)-derived epitopes. One epitope, α-syn32-46, binds with strong affinity to HLA-DRB1∗15:01 allele implicated in autoimmune diseases. We report α-syn32-46 immunization a mouse expressing human triggers intestinal inflammation, leading loss enteric neurons, damaged dopaminergic constipation,...
Abstract Modulation of the cervix by steroid hormones and commensal microbiome play a central role in health female reproductive tract. Here we describe organ-on-a-chip (Organ Chip) models that recreate human cervical epithelial-stromal interface with functional epithelial barrier production mucus biochemical hormone-responsive properties similar to living cervix. When Cervix Chips are populated optimal healthy versus dysbiotic microbial communities (dominated Lactobacillus crispatus...
This study explores the protective role of cervicovaginal mucus in maintaining vaginal health, particularly relation to bacterial vaginosis (BV), using organ chip technology. By integrating human Cervix and Vagina Chips, we demonstrated that cervical significantly reduces inflammation epithelial damage caused by a dysbiotic microbiome commonly associated with BV. Proteomic analysis Chip, following exposure from revealed differentially abundant proteins, suggesting potential biomarkers...
Abstract Focused ultrasound (FUS) with microbubbles opens the blood-brain barrier (BBB) to allow targeted drug delivery into brain. The mechanisms by which endothelial cells (ECs) respond either low acoustic pressures known open BBB transiently, or high that cause brain damage, remain incompletely characterized. Here, we use a mouse strain where tight junctions between ECs are labelled eGFP and apply FUS at (450 kPa) (750 pressures, after mice sacrificed 1 72 hours. We find EC response...
ABSTRACT Neurovascular unit and barrier maturation rely on vascular basement membrane (vBM) composition. Laminins, a major vBM component, are crucial for these processes, yet the signaling pathway(s) that regulate their expression remain unknown. Here, we show mural cells have active Wnt/β-catenin during central nervous system development in mice. Bulk RNA sequencing validation using postnatal day 10 14 wild-type versus adenomatosis polyposis coli downregulated 1 (Apcdd1−/−) mouse retinas...
Mucolipidosis IV (MLIV) is an ultra-rare, recessively inherited lysosomal disorder resulting from inactivating mutations in MCOLN1, the gene encoding cation channel TRPML1. The disease primarily affects central nervous system (CNS) and manifests first year with cognitive motor developmental delay, followed by a gradual decline neurological function across second decade of life, blindness, premature death third or fourth decades. Brain pathology manifestations MLIV are consistent...
SUMMARY The stability of tight junctions (TJs) between endothelial cells (ECs) is essential to maintain blood-brain barrier (BBB) function in the healthy brain. Following ischemic stroke, TJ strand dismantlement due protein degradation leads BBB dysfunction, yet mechanisms driving this process are poorly understood. Here, we show that endothelial-specific ablation Rab7a, a small GTPase regulates endolysosomal degradation, reduces stroke-induced disassembly resulting decreased paracellular...
ABSTRACT Modulation of mucus production by the human endo– and ecto-cervical epithelium steroid hormones associated interactions with commensal microbiome play a central role in physiology pathophysiology female reproductive tract. However, most our knowledge about these is based on results from animal studies or vitro models that fail to faithfully mimic mucosal environment cervix. Here we describe microfluidic organ-on-a-chip (Organ Chip) cervical mucosa recreate epithelial-stromal...
ABSTRACT Background The cervicovaginal mucus that coats the upper surface of vaginal epithelium is thought to serve as a selective barrier helps clear pathogens, however, its role in modulating physiology and pathophysiology human vagina poorly understood. Bacterial vaginosis (BV), common disease female reproductive tract increases susceptibility sexually transmitted infections, pelvic inflammatory disease, infertility, preterm birth, both maternal neonatal infections characterized by...
Abstract Background The cervicovaginal mucus which coats the upper surface of vaginal epithelium is thought to serve as a selective barrier that helps clear pathogens, however, its role in modulating physiology and pathophysiology human vagina poorly understood. Bacterial vaginosis (BV), common disease female reproductive tract increases susceptibility sexually transmitted infections, pelvic inflammatory disease, infertility, preterm birth, both maternal neonatal infections characterized by...
ABSTRACT Flavonoids are phytonutrients commonly found in plant-based foods and generally known for their health benefits. However, utility as potential therapeutics has not been explored because presence drug development tests can lead to false positives due non-specific binding. Here, we employed molecular dynamic simulations (MDS) examine flavonoid behavior discovered that they form highly organized supramolecular assemblies physically interact with disordered regions of enzymatic proteins...
SUMMARY Enteric symptoms, including constipation, are hallmarks of prodromal Parkinson’s disease (PD) that can appear decades before the onset motor symptoms and diagnosis. PD patients possess circulating T cells recognize specific α-synuclein-(α-syn)-derived epitopes. One epitope, α-syn 32-46 , binds with strong affinity to HLA-DRB1*15:01 allele implicated in autoimmune diseases. We report immunization a mouse expressing triggers intestinal inflammation leading loss enteric neurons, damage...
ABSTRACT Histopathological studies of multiple sclerosis (MS), a demyelinating disease the central nervous system (CNS), and its animal model, experimental autoimmune encephalomyelitis (EAE), have found newly formed leaky vessels in demyelinated acute chronic plaques, addition to blood-brain barrier (BBB) damage existing vessels, that exacerbate pathology by increasing infiltration immune cells. Which vessel subtypes signaling pathways generate these aberrant is poorly understood. Using...
Abstract 1 Mucolipidosis IV (MLIV) is an ultra-rare, recessively inherited lysosomal disorder resulting from inactivating mutations in MCOLN1 , the gene encoding cation channel TRPML1. The disease primarily affects central nervous system (CNS) and manifests first year with cognitive motor developmental delay, followed by a gradual decline neurological function across second decade of life, blindness, premature death third or fourth decades. Brain pathology manifestations MLIV are consistent...
SUMMARY Interactions among neuronal, glial and vascular components are crucial for retinal angiogenesis blood-retinal barrier (BRB) maturation. Although synaptic dysfunction precedes abnormalities in many pathologies, how neuronal activity, specifically glutamatergic regulates BRB maturation remains unclear. Using vivo genetic studies mice, single-cell RNA-sequencing functional validation, we show that deep plexus paracellular delayed Vglut1 -/- retinas where neurons fail to release...
Abstract Mucolipidosis IV (MLIV) is a rare, autosomal recessive, lysosomal disease characterized by intellectual disability, motor deficits and progressive vision loss. Using AAV9 AAV-PHP.B as delivery vectors, we previously demonstrated the feasibility of modifying course in mouse model MLIV human MCOLN1 gene transfer. Here, using primate-enabling capsid AAV.CPP.16 (CPP16), constructed new, clinic-oriented expression vector its efficacy preclinical MLIV. Systemic administration CPP16- adult...
ABSTRACT Neurovascular unit (NVU) assembly and barrier maturation rely on vascular basement membrane (vBM) composition. Laminins, a major vBM component, are critical for these processes, yet which signaling pathway(s) regulate their expression remains unknown. Here we show that mural cells have active Norrin/β-catenin during central nervous system development. Bulk RNA sequencing validation using P10 P14 wild-type versus Apcdd1 -/- retinas reveal Lama2 (Laminin-α2 chain) mRNA protein levels...