Children's Hospital Oakland Research Institute

About: Children's Hospital Oakland Research Institute is a based out in . It is known for research contribution in the topics: Population & Human leukocyte antigen. The organization has 1568 authors who have published 2480 publications receiving 203418 citations.

HNRNPA1 regulates HMGCR alternative splicing and modulates cellular cholesterol metabolism

Abstract: 3-hydroxy-3-methylglutaryl-CoenzymeAreductase(HMGCR)encodestherate-limitingenzymeinthecholesterol biosynthesispathway and isinhibited by statins,a class ofcholesterol-lowering drugs.Expression ofanalternatively spliced HMGCR transcript lacking exon 13, HMGCR13(2), has been implicated in the variation of plasma LDL-cholesterol (LDL-C) and is the single most informative molecular marker of LDL-C response to statins. Giventhe physiological importanceofthistranscript,our goal was toidentifymolecules thatregulateHMGCRalternative splicing.We recently reported gene expressionchanges in 480 lymphoblastoid cell lines (LCLs) afterin vitro simvastatin treatment, and identified a number of statin-responsive genes involved in mRNA splicing. Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) was chosen for follow-up since rs3846662, an HMGCR SNP that regulates exon 13 skipping, was predicted to alter an HNRNPA1 binding motif. Here, we not onlydemonstratethatrs3846662modulatesHNRNPA1binding,butalsothatsteroldepletionofhumanhepatoma cell lines reduced HNRNPA1 mRNA levels, an effect that was reversed with sterol add-back. Overexpression of HNRNPA1increasedtheratioofHMGCR13(2)tototalHMGCRtranscriptsbybothdirectlyincreasingexon13skipping in an allele-related manner and specifically stabilizing the HMGCR13(2) transcript. Importantly, HNRNPA1 overexpressionalsodiminishedHMGCRenzymeactivity,enhancedLDL-Cuptakeandincreasedcellularapolipoprotein B (APOB). rs1920045, an SNP associated withHNRNPA1 exon 8 alternative splicing, was also associated with smaller statin-induced reduction in total cholesterol from two independent clinical trials. These results suggest that HNRNPA1 plays a role in the variation of cardiovascular disease risk and statin response.

Nanobiotechnology applications of reconstituted high density lipoprotein

Abstract: High-density lipoprotein (HDL) plays a fundamental role in the Reverse Cholesterol Transport pathway. Prior to maturation, nascent HDL exist as disk-shaped phospholipid bilayers whose perimeter is stabilized by amphipathic apolipoproteins. Methods have been developed to generate reconstituted (rHDL) in vitro and these particles have been used in a variety of novel ways. To differentiate between physiological HDL particles and non-natural rHDL that have been engineered to possess additional components/functions, the term nanodisk (ND) is used. In this review, various applications of ND technology are described, such as their use as miniature membranes for solubilization and characterization of integral membrane proteins in a native like conformation. In other work, ND harboring hydrophobic biomolecules/drugs have been generated and used as transport/delivery vehicles. In vitro and in vivo studies show that drug loaded ND are stable and possess potent biological activity. A third application of ND is their use as a platform for incorporation of amphiphilic chelators of contrast agents, such as gadolinium, used in magnetic resonance imaging. Thus, it is demonstrated that the basic building block of plasma HDL can be repurposed for alternate functions.

Laboratory Correlates of Protection against Haemophilus influenzae Type b Disease.

Abstract: The concentration of serum antibody to the Haemophilus influenzae type b polysaccharide sufficient to confer protection against Hib disease has been estimated to range from 0.15 to 1.0 microgram/ml as measured by conventional antigen binding assays. However, the ability of these serologic tests to predict vaccine equivalence and/or protective efficacy is limited since there are important qualitative differences in vaccine-induced anti-PRP antibody, such as isotype, variable region usage, and antibody avidity. These differences may profoundly affect the biologic activity of the antibody. Also, Hib conjugate vaccination primes infants for memory antibody responses to a subsequent encounter with PRP, and immunologic priming can occur in infants with very low serum anti-PRP antibody responses to conjugate vaccination, or in those whose antibody concentrations have declined after vaccination. Primed infants are likely to be protected against Hib disease in the absence of "protective" serum antibody concentrations because priming permits a rapid serum anti-PRP antibody response upon encountering the organism. Thus, quantitative assessment of immunogenicity, by itself, is insufficient to predict vaccine equivalence or protective efficacy. In defining surrogate serologic tests for prediction of vaccine efficacy, assessments of antibody avidity and induction of immunologic memory should be included. Ideally, these assessments should be supplemented with antibody functional assays such as complement-mediated bactericidal activity, opsonic activity, or passive protection in animal models of disease.