Research
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Overview
The Rader lab leverages human genetics of a wide range of cardiometabolic diseases and traits as well as Alzheimer’s disease to identify new variants, genes, and pathways that underlie these phenotypes. The lab uses a variety of experimental systems including mice, cell lines, human induced pluripotent stem cells, and humans to elucidate the molecular mechanisms by which these genes and pathways influence these phenotypes. In addition to elucidating fundamental mechanisms by which the protein influences relevant biology, the influence of specific mutations on protein structure and function are being explored. The lab makes use of the Penn Medicine Biobank, a large academic biobank with large-scale whole exome data linked to EHR phenotype data, for genetic discovery, biomarker studies, and ‘recall-by-genotype’ deep phenotyping studies. In addition to generating new insights in human biology and disease, the lab also works on translational therapeutics targeting these genes and pathways for cardiometabolic disease.
Currently Active Research Projects
Structure-function and physiology of APOA5, a natural activator of lipoprotein lipase
APOA5 is a liver-secreted protein with strong genetic association to plasma triglycerides and coronary artery disease. This project integrates protein structure-mapping, biophysical studies, natural human genetic variants, and functional studies in vivo and in vitro to inform structure-function and mechanism of ApoA5.
Molecular and physiological role of PPP1R3B in liver disease, lipoprotein metabolism, and Alzheimer’s disease
Genetic variants at the PPP1R3B gene locus are significantly associated with plasma lipids, steatotic liver disease, and Alzheimer’s disease. Our work suggests that PPP1R3B acts as a circadian metabolic switch and bidirectional mediator of liver injury. Our ongoing studies in mice and cell models are designed to elucidate how alterations in hepatic PPP1R3B expression influences hepatic lipid metabolism and liver injury. In parallel studies, we are exploring the roles of hepatocyte and microglia PPP1R3B expression on Alzheimer’s disease phenotypes, including the potential involvement of PPP1R3B in circadian regulation.
Molecular mechanisms by which ABCA7 and ABCA1 activity influence Alzheimer's disease
ABCA1 and ABCA7 are related members of the ATP-binding cassette transporter subfamily A (ABCA) that exports lipid species out of cells. Human genetics has firmly associated genetic variants that reduce their activity with increased risk of Alzheimer’s disease. This project seeks to specifically elucidate the structure and function of ABCA7, the lipids it transports and in which cells, and to clarify its role in contributing to AD pathogenesis. ABCA1 will be studied in parallel. The primary model system is human iPSCs engineered to be deleted in either ABCA7 or ABCA1 and then differentiated to microglia, astrocytes and neurons to establish the effects on AD-relevant functions in these cells. Additional studies are aimed at a) identifying ABCA7 protein domains that distinguish it with regard to specificity of lipid translocase activities; b) in vitro characterization of the functional effects of naturally-occurring ABCA7 coding variants that are significantly associated with AD.
Functional interrogation of genes at GWAS loci associated with both plasma lipids and cardiovascular diseases
A large number of GWAS loci associated with plasma lipid traits are also associated with one or more major cardiovascular diseases, both atherosclerotic and non-atherosclerotic. The lab employs a variety of computational approaches to select and prioritize specific candidate causal genes at these loci, most of which do know harbor ‘known’ lipid genes. Candidate genes are overexpressed and silenced in the human liver cell line Huh7 as an additional screen and then prioritized genes are overexpressed and knocked down in mouse liver to assess lipid phenotypes and mechanisms. In addition, human induced pluripotent stem (iPSC) cells are CRISPR-engineered to delete genes of interest and differentiated to hepatocytes for phenotyping. In selected cases, multi-omics and deep phenotyping of somatic gene-targeted mice and stored plasma from PMBB participants carrying genetic variants of high interest are used to gain further insight into biology and mechanisms. In some cases, strategically-selected naturally-occurring protein-coding variants in genes of interest are studied compared to wild-type protein for insight into structure-function.
Functional interrogation of T2D-associated genes in human stem cell-derived models and mice
Human genetic studies have identified hundreds of type 2 diabetes (T2D)-associated genetic loci, but the mechanisms through which most of these loci affect disease susceptibility remain poorly understood. We are part of a multidisciplinary team performing comprehensive functional assessments of candidate T2D-effector transcripts in human cell and mouse models of diabetes with the goal of identifying new therapeutic avenues.
‘Genome-first’ deep phenotyping of human subjects with genetic variants of high interest
The lab leverages the extensive genomic data in the PMBB to perform ‘deep dives’ into genes of high interest. Participants with rare putative loss-of-function (pLOF) and computationally predicted deleterious missense variants are identified and compared with non-carrier controls through phenome-wide association studies (PheWAS) and other phenotypes are generated from the electronic health record through natural language processing and machine learning approaches. Stored plasma samples are utilized for multi-omics studies. In some cases, participants with rare variants of interest are invited to participate in additional ‘deep phenotyping’ studies that are customized to the gene and hypothesis. Given our particular interest in lipoprotein metabolism, we often perform ‘oral fat tolerance testing’ and even detailed assessment of lipoprotein kinetics using stable isotopically-labeled amino acids incorporated endogenously into newly-synthesized proteins.
Generation of imaging-derived phenotypes using machine learning for integration with genomics
Participants in the PMBB have had many imaging studies performed clinically and working with colleagues in radiology we have developed machine learning approaches to quantitating a wide range of imaging-derived phenotypes (IDPs) for use in discovery research, such as integration with genomic data. One example of this work focused on the quantitation of hepatic fat from CT scans, and we are applying this approach to a wide range of ID
Clinical research studies for which the Division of Translational Medicine and Human Genetics is recruiting subjects
NICE Study
The NICE study is a clinical research study to assess the effects of obicetrapib, an investigational drug, on lipoprotein metabolism in people with LDL-cholesterol levels between 100 and 190 mg/dL.
Participation in the study will last for approximately 11-18 weeks. It will involve a screening visit to assess your eligibility, two overnight, inpatient visits during which you will undergo a lipid metabolism study involving an infusion over 12 hours, eating multiple small meals, and having blood drawn several times through an IV (intravenous) catheter, and 3 short outpatient visits for follow-up labs.
You will be compensated for each study visit after the Screening visit if you qualify and enroll into the study. You will receive $2300 if you complete the entire study.
Contact NICEstudy@pennmedicine.upenn.edu if interested.
ISIS 678354-CS6
A study of olezarsen administered subcutaneously to patients with severe hypertriglyceridemia. This is a Phase 3, multi-center, randomized, double-blind, placebo-controlled study in up to approximately 390 participants. Participants will be randomized to receive olezarsen or placebo in a 53-week treatment period. The length of participation in the study will be approximately 78 weeks, which includes an up to 12-week screening period, a 53-week treatment period, and a 13-week post-treatment evaluation period or transition to open-label extension (OLE) study with up to 1-year treatment.
Eligible participants must have fasting triglyceride levels ≥ 500 mg/dL at both Screening and Qualification visits.
Contact anika.krishnan@pennmedicine.upenn.edu if interested.