A5018938435- Nuclear Structure and Function
- RNA Research and Splicing
- Mitochondrial Function and Pathology
- PARP inhibition in cancer therapy
- Metabolism and Genetic Disorders
- Cytokine Signaling Pathways and Interactions
- ATP Synthase and ATPases Research
- Atherosclerosis and Cardiovascular Diseases
- Telomeres, Telomerase, and Senescence
- Advanced Fluorescence Microscopy Techniques
- Ginkgo biloba and Cashew Applications
- NF-κB Signaling Pathways
- Coenzyme Q10 studies and effects
- Adipose Tissue and Metabolism
- Multiple Sclerosis Research Studies
- Cardiovascular Health and Disease Prevention
- Ubiquitin and proteasome pathways
- Cancer, Hypoxia, and Metabolism
- Immune Cell Function and Interaction
- Advanced battery technologies research
- Genomics and Chromatin Dynamics
- Signaling Pathways in Disease
- Advanced Biosensing Techniques and Applications
- Glycogen Storage Diseases and Myoclonus
- Genetics, Aging, and Longevity in Model Organisms
Centro de Investigación en Red en Enfermedades Cardiovasculares
2020-2024
Spanish National Centre for Cardiovascular Research
2015-2024
Centro de Investigación Biomédica en Red
2017-2024
Columbia University Irving Medical Center
2010-2012
Clark Art Institute
2009
Columbia University
2009
Centro Nacional de Microbiologia
2003-2007
Instituto de Salud Carlos III
1998-2007
<h3>Background</h3> Mutations in the glucocerebrosidase (<i>GBA</i>) gene are associated with Lewy body (LB) disorders. <h3>Objective</h3> To determine relationship of<i>GBA</i>mutations and<i>APOE4</i>genotype to LB and Alzheimer disease (AD) pathological findings. <h3>Design</h3> Case-control study. <h3>Setting</h3> Academic research. <h3>Participants</h3> The 187 subjects included patients primary neuropathological diagnoses of disorders or without AD changes (95 cases), randomly selected...
Coenzyme Q10 (CoQ10) is essential for electron transport in the mitochondrial respiratory chain and antioxidant defense. The relative importance of defects, ROS production, apoptosis pathogenesis CoQ10 deficiency unknown. We determined previously that severe cultured skin fibroblasts harboring COQ2 PDSS2 mutations produces divergent alterations bioenergetics oxidative stress. Here, to better understand deficiency, we have characterized effects varying severities on production cells genetic...
Replication and repair of DNA require equilibrated pools deoxynucleoside triphosphate precursors. This concept has been proven by in vitro studies over many years, but vivo models are required to demonstrate its relevance multicellular organisms human diseases. Accordingly, we have generated thymidine phosphorylase (TP) uridine (UP) double knockout (TP−/−UP−/−) mice, which show severe TP deficiency, increased deoxyuridine tissues elevated mitochondrial deoxythymidine triphosphate. As...
Mitochondrial DNA (mtDNA) depletion syndrome (MDS), an autosomal recessive condition, is characterized by variable organ involvement with decreased mtDNA copy number and activities of respiratory chain enzymes in affected tissues. MtDNA has been associated mutations nine genes, including thymidine kinase ( TK2 ), which encodes a ubiquitous mitochondrial protein. To study the pathogenesis TK2-deficiency, we generated mice harboring H126N Tk2 mutation. Homozygous mutant (Tk2 −/− ) developed...
Leucocyte telomere length (LTL) shortening is associated with cardiovascular ischemic events and mortality in humans, but data on its association subclinical atherosclerosis are scarce. Whether the incidence severity of abundance critically short telomeres, a major trigger cellular senescence, remains unknown. The authors conducted cross-sectional exploration between burden both average LTL telomeres (%LTL<3 kb). Telomere was assessed by high-throughput quantitative fluorescence situ...
Primary human CoQ10 deficiencies are clinically heterogeneous diseases caused by mutations in PDSS2 and other genes required for biosynthesis. Our vitro studies of mutant fibroblasts, with <20% control cells, revealed reduced activity CoQ10-dependent complex II+III ATP synthesis, without amplification reactive oxygen species (ROS), markers oxidative damage, or antioxidant defenses. In contrast, COQ2 ADCK3 30–50% controls, showed milder bioenergetic defects but significantly increased ROS...
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder for which no cure exists. The disease characterized by premature aging and inevitable death in adolescence due to cardiovascular complications. Most HGPS patients carry a heterozygous de novo LMNA c.1824C > T mutation, provokes the expression of dominant-negative mutant protein called progerin. Therapies proven effective HGPS-like mouse models have yielded only modest benefit clinical trials. To overcome gap...
Background: Hutchinson-Gilford progeria syndrome (HGPS) is a rare disorder characterized by premature aging and death mainly because of myocardial infarction, stroke, or heart failure. The disease provoked progerin, variant lamin A expressed in most differentiated cells. Patients look healthy at birth, symptoms typically emerge the first second year life. Assessing reversibility progerin-induced damage relative contribution specific cell types critical to determining potential benefits late...
Differentiation of naive CD4+ T-cells into functionally distinct T helper (Th) subsets is critical to immunity against pathogen infection. Little known about the role signals emanating from nuclear envelope for T-cell differentiation. The protein lamin A/C induced in upon antigen recognition and acts as a link between nucleus plasma membrane during activation. Here we demonstrate that absence reduces Th1 differentiation without affecting Th2 vitro vivo. Moreover, Rag1 -/- mice reconstituted...
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare disease caused by the expression of progerin, aberrant protein produced a point mutation in LMNA gene. HGPS patients show accelerated aging and die prematurely mainly from complications atherosclerosis such as myocardial infarction, heart failure, or stroke. However, mechanisms underlying vascular pathology remain ill defined. We used single-cell RNA sequencing to characterize aorta progerin-expressing LmnaG609G/G609G mice...
Cardiovascular disease (CVD) is the main cause of death worldwide, and aging its leading risk factor. Aging much accelerated in Hutchinson–Gilford progeria syndrome (HGPS), an ultra-rare genetic disorder provoked by ubiquitous expression a mutant protein called progerin. HGPS patients die their teens, primarily due to cardiovascular complications. The primary causes age-associated CVD are endothelial dysfunction dysregulated vascular tone; however, contribution progerin-induced remains...
Deficiency of thymidine kinase 2 (TK2) is a frequent cause isolated myopathy or encephalomyopathy in children with mitochondrial DNA (mtDNA) depletion. To determine the bases disease onset, organ specificity and severity TK2 deficiency, we have carefully characterized Tk2 H126N knockin mice (Tk2-/-). Although normal until postnatal day 8, Tk2-/- rapidly develop fatal between days 10 13. We observed that wild-type activity constant second week life, while Tk1 decreases significantly 8 The...
Hutchinson–Gilford progeria syndrome (HGPS) is a rare disease caused by the expression of progerin, mutant protein that accelerates aging and precipitates death. Given atherosclerosis complications are main cause death in progeria, here, we investigated whether progerin-induced prevented HGPSrev-Cdh5-CreERT2 HGPSrev-SM22α-Cre mice with progerin suppression endothelial cells (ECs) vascular smooth muscle (VSMCs), respectively. were undistinguishable from HGPSrev ubiquitous expression, contrast...
Mammal adipose tissues require mitochondrial activity for proper development and differentiation. The components of the respiratory chain/oxidative phosphorylation system (OXPHOS) are encoded by both nuclear genomes. maintenance DNA (mtDNA) is a key element functional oxidative in mammalian cells. To ascertain role mtDNA levels tissue, we have analyzed alterations white (WAT) brown (BAT) thymidine kinase 2 (Tk2) H126N knockin mice, model TK2 deficiency-induced depletion. We observed...
Aging is the main risk factor for cardiovascular and metabolic diseases, which have become a global concern as world population ages. These diseases aging process are exacerbated in Hutchinson-Gilford progeria syndrome (HGPS or progeria). Here, we evaluated cardiometabolic disease animal models of premature normal with aim identifying alterations that shared specific to each condition. Despite differences body composition markers, prematurely normally mice developed heart failure similar...
Abstract Hutchinson‐Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by mutation in the LMNA gene that provokes synthesis of progerin, mutant version nuclear protein lamin A accelerates aging and precipitates death. The most clinically relevant feature HGPS development cardiac anomalies severe vascular alterations, including massive loss smooth muscle cells, increased fibrosis, generalized atherosclerosis. However, it unclear if progerin expression endothelial cells (ECs)...