A5023925110- Alzheimer's disease research and treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- Bioinformatics and Genomic Networks
- Epigenetics and DNA Methylation
- Developmental Biology and Gene Regulation
- Single-cell and spatial transcriptomics
- Neuroblastoma Research and Treatments
- Inflammasome and immune disorders
- Hedgehog Signaling Pathway Studies
- Genetics and Neurodevelopmental Disorders
- Immune cells in cancer
- ATP Synthase and ATPases Research
- Stress Responses and Cortisol
- Glycosylation and Glycoproteins Research
- Dementia and Cognitive Impairment Research
- Reproductive Biology and Fertility
- Neuroscience and Neuropharmacology Research
- Congenital limb and hand anomalies
- Tendon Structure and Treatment
- Semantic Web and Ontologies
- interferon and immune responses
- Tryptophan and brain disorders
- Growth Hormone and Insulin-like Growth Factors
- Inorganic Fluorides and Related Compounds
- Hormonal Regulation and Hypertension
Harvard University
2006-2025
Brigham and Women's Hospital
2017-2025
Columbia University Irving Medical Center
2022
Pacific Northwest National Laboratory
2022
Rush University Medical Center
2022
Harvard University Press
2022
Emory University
2022
Eagle Mount
2012
University of California, San Diego
1993-1997
Howard Hughes Medical Institute
1993-1997
ABSTRACT Reactive astrocytes are associated with Alzheimer's disease (AD), and several AD genetic risk variants genes highly expressed in astrocytes. However, the contribution of within to cellular processes relevant pathogenesis remains ill‐defined. Here, we present a resource for studying using large collection induced pluripotent stem cell (iPSC) lines from deeply phenotyped individuals range neuropathological cognitive outcomes. IPSC 44 were differentiated into followed by unbiased...
Corticotropin-releasing factor (CRF) mediates many critical aspects of the physiological response to stress. These effects are elicited by binding specific high-affinity receptors, which coupled guanine nucleotide stimulatory (Gs)-response pathways. Recently, a gene encoding receptor for CRF, expressed in pituitary and central nervous system (PC-CRF receptor), was isolated characterized. Here we report identification characterization second, distinct CRF that is primarily heart skeletal...
A pituitary LIM homeodomain factor, P-Lim, is expressed as Rathke's pouch forms and specific cell phenotypes are established, suggesting functional roles throughout development. While selectively in both anterior intermediate mature mice, P-Lim also transiently the developing ventral neural cord brainstem. binds to activates promoter of alpha-glycoprotein subunit gene, a marker early development, synergizes with Pit-1 transcriptional activation genes encoding terminal differentiation...
Abstract Microglia and neuroinflammation play an important role in the development progression of Alzheimer’s disease (AD). Inositol polyphosphate-5-phosphatase D ( INPP5D/SHIP1 ) is a myeloid-expressed gene genetically-associated with AD. Through unbiased analyses RNA protein profiles INPP5D-disrupted iPSC-derived human microglia, we find that reduction INPP5D activity associated molecular consistent disrupted autophagy inflammasome activation. These findings are validated through targeted...
SORL1 is implicated in the pathogenesis of Alzheimer's disease (AD) through genetic studies. To interrogate roles human brain cells, SORL1-null induced pluripotent stem cells (iPSCs) were differentiated to neuron, astrocyte, microglial, and endothelial cell fates. Loss leads alterations both overlapping distinct pathways across types, with greatest effects neurons astrocytes. loss induces a neuron-specific reduction apolipoprotein E (APOE) clusterin (CLU) altered lipid profiles. Analyses...
Alzheimer's disease (AD) induces memory and cognitive impairment in the absence of motor sensory deficits during its early middle course. A major unresolved question is basis for this selective neuronal vulnerability. Aβ, which plays a central role AD pathogenesis, generated throughout brain, yet some regions outside limbic cerebral cortices are relatively spared from Aβ plaque deposition synapse loss. Here, we examine neurons derived iPSCs patients harboring an amyloid precursor protein...
Mosaic loss of Chromosome Y (LOY) is a common acquired structural mutation in the leukocytes aging men that correlated with several age-related diseases, including Alzheimer's disease (AD). The molecular basis LOY brain cells has not been systematically investigated. Here, we present large-scale analysis single-cell and single-nuclei RNA data sets, yielding 851,674 cells, to investigate cell type–specific burden LOY. frequencies differed widely between donors CNS types. Among five...
Abstract The relationship between genetic variation and gene expression in individual brain cell types subtypes has remained elusive. Here, we generated single-nucleus RNA sequencing data from the dorsolateral prefrontal cortex of 424 individuals advanced age; analyzing 1.5 million nuclear transcriptomes, assessed effect variants on cis ( -eQTL) for 7 81 subtypes. This effort identified 10,004 eGenes at type level 8,138 subtype level. Many are only detected within A new variant influences...
Abstract BACKGROUND Impairment of the ubiquitin‐proteasome system (UPS) has been implicated in abnormal protein accumulation Alzheimer's disease. It remains unclear if genetic variation affects intrinsic properties neurons that render some individuals more vulnerable to UPS impairment. METHODS Induced pluripotent stem cell (iPSC)‐derived were generated from over 50 genetically variant and highly characterized participants cohorts aging. Proteomic profiling, proteasome activity assays,...
Abstract Despite decades of genetic studies on late-onset Alzheimer’s disease, the underlying molecular mechanisms remain unclear. To better comprehend its complex etiology, we use an integrative approach to build robust predictive (causal) network models using two large human multi-omics datasets. We delineate bulk-tissue gene expression into single cell-type and integrate clinical pathologic traits, nucleotide variation, deconvoluted for construction cell type-specific models. Here, focus...
Signals that instruct the developing limb bud mesenchyme to form appropriate elements along anterior posterior axis emanate from zone of polarizing activity (ZPA). Studies last five years have illustrated Sonic hedgehog (Shh) protein mediates activities ZPA. This review will focus on three aspects ZPA biology. We address induction in terms factors required for activation and maintenance Shh expression evidence negative regulatory mechanisms prevent inappropriate expression. Second, we...
Members of the POU-homeodomain gene family encode transcriptional regulatory molecules that play important roles in terminal differentiation many organ systems. Sperm-1 (Sprm-1) is a POU domain factor exclusively expressed differentiating male germ cell. We show here Sprm-1 protein haploid spermatid and 129/Sv ( −/− ) mice are subfertile when compared with wild-type or heterozygous littermates yet exhibit normal testicular morphology produce numbers mobile spermatozoa. Our data suggest plays...
We have identified rat cDNA clones that encode a POU domain protein, referred to as brain-5 (Brn-5). During embryogenesis in the rat, Brn-5 is widely expressed with highest levels developing brain and spinal cord from embryonic day 12.5. In adult, mRNA most abundant brain, where it diffusely exception of an enrichment layer IV neocortex. However, also found multiple adult tissues outside central nervous system, including kidney, lung, heart, adrenal, skin, testis, anterior pituitary. This...