A5067718720- Regulation of Appetite and Obesity
- Biochemical Analysis and Sensing Techniques
- Pluripotent Stem Cells Research
- Adipokines, Inflammation, and Metabolic Diseases
- Neurogenesis and neuroplasticity mechanisms
- Epigenetics and DNA Methylation
- CRISPR and Genetic Engineering
- Adipose Tissue and Metabolism
- Advanced MRI Techniques and Applications
- Advanced Neuroimaging Techniques and Applications
- MRI in cancer diagnosis
- Genetic Associations and Epidemiology
- Genetic Syndromes and Imprinting
- Congenital heart defects research
- 3D Printing in Biomedical Research
- Single-cell and spatial transcriptomics
- Pancreatic function and diabetes
- Genomics and Chromatin Dynamics
- Genetic and Kidney Cyst Diseases
- Bone and Joint Diseases
- Cellular transport and secretion
- Circadian rhythm and melatonin
- Alzheimer's disease research and treatments
- Medical Imaging Techniques and Applications
- Acute Ischemic Stroke Management
Columbia University
2011-2024
Columbia University Irving Medical Center
2009-2023
Stem Cell Institute
2021
Royal College of Physicians
2020-2021
Columbia College
2020
Charité - Universitätsmedizin Berlin
2000-2004
Humboldt-Universität zu Berlin
2000-2004
Memorial Sloan Kettering Cancer Center
2003
The University of Melbourne
2003
Klinik und Poliklinik für Neurologie
2000
The development and diversity of neuronal subtypes in the human hypothalamus has been insufficiently characterized. To address this, we integrated transcriptomic data from 241,096 cells (126,840 newly generated) prenatal adult to reveal a temporal trajectory proliferative stem cell populations mature hypothalamic types. Iterative clustering neurons identified 108 robust transcriptionally distinct representing 10 nuclei. Pseudotime trajectories provided insights into genes driving formation...
Frontotemporal dementia (FTD) is an incurable group of early-onset dementias that can be caused by the deposition hyperphosphorylated tau in patient brains. However, mechanisms leading to neurodegeneration remain largely unknown. Here, we combined single-cell analyses FTD brains with a stem cell culture and transplantation model FTD. We identified disease phenotypes neurons carrying MAPT-N279K mutation, which were related oxidative stress, phosphorylation, neuroinflammation upregulation...
To uncover novel significant association signals (p<5×10 −8 ), genome-wide studies (GWAS) requires increasingly larger sample sizes to overcome statistical correction for multiple testing. As an alternative, we aimed identify associations among suggestive (5 × 10 ≤p<5×10 −4 ) in powered GWAS efforts using chromatin accessibility and direct contact with gene promoters as biological constraints. We conducted retrospective analyses of three GIANT BMI ATAC-seq promoter-focused Capture C...
SNAREs (soluble N -ethylmaleimide-sensitive factor attachment protein receptors) are central components of the machinery mediating membrane fusion in all eukaryotic cells. Sequence analysis yeast genome revealed a previously uncharacterized SNARE, S NARE- l ike t ail-anchored 1 (Slt1). Slt1 is an essential localized endoplasmic reticulum (ER). It forms SNARE complex with Sec22 and ER syntaxin Ufe1. Down-regulation levels leads to improper secretion proteins normally resident ER. We suggest...
Leptin influences food intake by informing the brain about status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated administering leptin. However, role genetic regulation in polygenic remains poorly understood. We performed an exome-based analysis up to 57,232 individuals diverse ancestries identify variants influence adiposity-adjusted concentrations. five novel variants, including four missense LEP,...
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder caused by mutations in genes encoding components of the primary cilium and characterized hyperphagic obesity. To investigate molecular basis obesity human BBS, we developed cellular model BBS using induced pluripotent stem cell-derived (iPSC-derived) hypothalamic arcuate-like neurons. BBS1M390R BBS10C91fsX95 did not affect neuronal differentiation efficiency but morphological defects, including impaired neurite outgrowth...
Abstract The hypothalamus regulates metabolic homeostasis by influencing behavior and endocrine systems. Given its role governing key traits, such as body weight reproductive timing, understanding the genetic regulation of hypothalamic development function could yield insights into disease pathogenesis. However, given inaccessibility, studying human gene has proven challenging. To address this gap, we generate a high-resolution chromatin architecture atlas an established embryonic stem cell...
A new functional class of SNAREs, designated inhibitory SNAREs (i-SNAREs), is described here. An i-SNARE inhibits fusion by substituting for or binding to a subunit fusogenic SNAREpin form nonfusogenic complex. Golgi-localized were tested activity adding them as fifth SNARE together with four other that mediate Golgi reactions. striking pattern emerges in which certain subunits the cis-Golgi function i-SNAREs inhibit mediated trans-Golgi SNAREpin, and vice versa. Although opposing...
Intronic polymorphisms in the α-ketoglutarate–dependent dioxygenase gene (FTO) that are highly associated with increased body weight have been implicated transcriptional control of a nearby ciliary gene, retinitis pigmentosa GTPase regulator-interacting protein-1 like (RPGRIP1L). Previous studies shown congenital Rpgrip1l hypomorphism murine proopiomelanocortin (Pomc) neurons causes obesity by increasing food intake. Here, we show and adult-onset deletion Pomc-expressing hyperphagia likely...
Bassoon (BSN) is a component of hetero-dimeric presynaptic cytomatrix protein that orchestrates neurotransmitter release with Piccolo (PCLO) from glutamatergic neurons throughout the brain. Heterozygous missense variants in BSN have previously been associated neurodegenerative disorders humans. We performed an exome-wide association analysis ultra-rare about 140,000 unrelated individuals UK Biobank to search for new genes obesity. found rare heterozygous predicted loss function (pLoF) are...
In spite of marked disability, patients with primary progressive multiple sclerosis (PPMS) display smaller lesion volumes on conventional magnetic resonance imaging (MRI) compared other forms (MS). Hence, damage to the normal-appear ing brain tissue (NA BT) may play an important role in explaining patho genesis disability PPMS. Diffusion-weighted MRI (DW-MRI) probes water diffusion vivo that can be altered by logic changes. Using DW-MRI we investigated NA BT 15 PPMS over one year. The...
Highlights•Stem cell-derived hypothalamic neurons are used to study human obesity•shRNA and CRISPR-Cas9 were generate models of PCSK1 deficiency•PC1/3 deficiency impaired POMC processing in arcuate-like neurons•Adaptive changes occurred "downstream" enzymesSummaryWe recently developed a technique for generating from pluripotent stem cells. Here, as proof principle, we examine the use these cells modeling monogenic form severe obesity: deficiency. The cognate enzyme, PC1/3, processes many...
Mutations in melanocortin receptor (MC4R) are the most common cause of monogenic obesity children European ancestry, but little is known about their prevalence from minority populations United States.This study aims to identify MC4R mutations with severe early-onset African American or Latino ancestry.Participants were recruited weight management clinics at two hospitals and institutional biobank a third hospital. Sequencing gene was performed by whole exome Sanger sequencing. Functional...
Background & AimsInflammatory bowel disease (IBD) is a polygenic disorder characterized principally by dysregulated inflammation impacting the gastrointestinal tract. However, there also increasing evidence for clinical association with stress and depression. Given role of hypothalamus in responses pathogenesis depression, useful insights could be gleaned from understanding its genetic IBD.MethodsWe conducted correlation analyses on publicly available genome-wide study summary statistics...
Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein-9 (Cas9) has become the tool of choice for genome editing. Despite fact that it evolved as a highly efficient means to edit/replace coding sequence, CRISPR/Cas9 efficiency "clean" editing non-coding DNA remains low. We set out introduce single base-pair substitution in two intronic SNPs at FTO locus without altering nearby sequence. Substitution increased up 10-fold by treatment human embryonic stem...
Energy balance is controlled by interconnected brain regions in the hypothalamus, brainstem, cortex, and limbic system. Gene expression signatures of these can help elucidate pathophysiology underlying obesity. RNA sequencing was conducted on P56 C57BL/6NTac male mice E14.5 embryo punch biopsies 16 obesity-relevant regions. The 190 known obesity-associated genes (monogenic, rare, low-frequency coding variants; GWAS; syndromic) analyzed each anatomical region. Genes associated with genetic...
Six patients who had suffered small cerebral ischemia affecting subcortical gray matter were examined with diffusion weighted imaging (DWI) and T2-weighted within the first 8 h, during next 2 days after 5–16 days. Areas of apparent coefficient (ADC) decreases observed acutely reached maximum size subsequent Noticeably, in all subjects, a large portion ADC lesion was reversible as judged from on final T2 image. The regular reversibility this setting may indicate hitherto not understood...