NIH Studies

The U.S. National Institutes of Health (NIH) has engaged Vala Sciences to complete the following research programs utilizing Vala’s technology platform.  Additional detail for each project can viewed by clicking the NIH link button in each project’s description.

Neuroscience

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Project Number: AG062012

Project Title: The Alzheimer’s Therapeutics Screening Assay: a high-throughput drug-discovery platform utilizing neurons and microglia derived from human induced pluripotent stem cells and Kinetic Image Cytometry

Project Description:

No new drug for Alzheimer’s Disease has been approved since 2003, highlighting the need for more predictive preclinical drug discovery systems. This project aims to develop the Alzheimer’s Therapeutics Screening Assay (ATSA) using co-cultures of neurons, microglia, and astrocytes derived from human induced pluripotent stem cells. We will expose these cultures to Alzheimer’s-relevant stressors like amyloid beta oligomers, apolipoprotein E-isoform 4 fragments, and excitotoxic agents. We will then assay each cell type for changes in morphology, synapses, and calcium and voltage activity. The results from this research will enable the ATSA to identify compounds that ameliorate Alzheimer’s neurotoxicity.

Funding agency: NIH/National Institute on Aging

Award Date: September 2018

 

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Project Number: MH119621

Project Title: The Microscopic Imaging of Epigenetic Landscape-NeuroDevelopment (MIEL-ND) assay: a high throughput platform to screen compounds for neurodevelopmental effects

Project Description:

Recent research suggests that neurodevelopmental diseases (Autism Spectrum Disorder, intellectual disabilities, bipolar disorders, schizophrenia, etc.) can result from disruption of epigenetic histone and DNA modification by prenatal exposure to environmental toxicants. This project will develop the Microscopic Imaging of Epigenetic Landscape – NeuroDevelopment (MIEL-ND) assay, which will enable testing of chemicals for epigenetic effects on neurodevelopment. The MIEL-ND assay will use immunolabeling, automated high-throughput imaging, and cell-by-cell analysis to screen chemicals in the US EPA ToxCast program for effects epigenetic modification patterns in human neural precursor cells. The assay will also screen for effects on neurite and synapse formation in neurons derived from human induced pluripotent stem cells. The MIEL-ND assay will provide a less expensive, higher throughput, and more predictive alternative to animal testing.

Funding agency: NIH/National Institute of Mental Health

Award Date: September 2018

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Project Number: ES026268

Project Title: Assay of environmental toxicants for toxicity related to Alzheimer’s Disease utilizing human iPSC-derived- neurons and microglia

Project Description:

Particulate air pollution 2.5 microns in diameter or less (PM2.5 particles) can enter the human body through the respiratory system and directly or indirectly damage the brain. High concentrations of PM2.5 particles in heavily polluted areas have been linked to increased Alzheimer’s Disease incidence. This project aims to increase our understanding of how PM2.5 particles cause neurodegeneration. We will investigate the effects of PM2.5 particles on neurons and microglia derived from human induced pluripotent stem cells. We will assay cells with multiple genotypes, including those expressing the epsilon-4 variant of apolipoprotein E, which increases risk of late-onset Alzheimer’s and likely increase susceptibility to environmental toxicants. This assay system will also be useful in identifying therapeutics for Alzheimer’s and other neurodegenerative diseases.

Funding agency: NIH/National Institute of Environmental Health Sciences

Award Date: September 2018

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Project Number: ES026268

Project Title: Assay of chemicals for Parkinson’s toxicity in human iPSC-derived neurons

Project Description:

Environmental toxicants like rotenone, paraquat, or maneb can increase risk of Parkinson’s Disease. This project aims to develop an assay system to screen environmental toxicants for potential Parkinson’s toxicity. Our assay will detect toxicity in dopaminergic neurons (the main cell type affected by Parkinson’s) and microglia derived from human induced pluripotent stem cells. We will test each toxicant for effects on Parkinson’s-associated protein aggregation, mitochondrial function, and calcium and voltage activity. The resulting assay system will enable comprehensive and clinically relevant screening for toxicants with potential Parkinson’s-inducing effects.

Funding agency: NIH/National Institute of Environmental Health Sciences

Award Date: September 2015

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Project Number: AG062012

Project Title: The Alzheimer’s Therapeutics Screening Assay: a high-throughput drug-discovery platform utilizing neurons and microglia derived from human induced pluripotent stem cells and Kinetic Image Cytometry

Project Description:

No new drug for Alzheimer’s Disease has been approved since 2003, highlighting the need for more predictive preclinical drug discovery systems. This project aims to develop the Alzheimer’s Therapeutics Screening Assay (ATSA) using co-cultures of neurons, microglia, and astrocytes derived from human induced pluripotent stem cells. We will expose these cultures to Alzheimer’s-relevant stressors like amyloid beta oligomers, apolipoprotein E-isoform 4 fragments, and excitotoxic agents. We will then assay each cell type for changes in morphology, synapses, and calcium and voltage activity. The results from this research will enable the ATSA to identify compounds that ameliorate Alzheimer’s neurotoxicity.

Funding agency: NIH/National Institute on Aging

Award Date: September 2018

 

Cardiac Biology

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Project Number: ES023521

Project Title: Stem cell toxicology assays for cardiac differentiation

Project Description:

Environmental toxicants can disrupt fetal heart formation and lead to miscarriages or congenital heart defects. Little is known about how such chemicals might affect early heart development. This project aims to develop a Cardiopoiesis (heart formation) Assay to screen for compounds that influence the differentiation of cardiomyocyte precursors from multipotent mesodermal progenitors. The Cardiopoiesis Assay will test for compound effects on the ability of multipotent mesodermal progenitors derived from human induced pluripotent stem cells to express MYH6, a cardiac-specific gene, or markers of alternative cell fates. This assay will provide a less expensive, higher throughput, and more predictive alternative to animal testing.

Funding agency: NIH/National Institute of Environmental Health Sciences

Award Date: September 2013

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Project Number: HL112521

Project Title: Optogenetic Multiparametric Assay for HT Cardiotoxicity Testing

Project Description:

Many drug candidates fail in clinical trials or after market launch due to cardiotoxicity, highlighting the need for more predictive preclinical cardiosafety screens. This project aims to develop a high throughput cardiosafety screening platform using cardiomyocytes derived from human induced pluripotent stem cells, which exhibit the contractile phenotype of human ventricular cardiomyocytes. Following compound exposure, we will use automated microscopy and image analysis to quantify calcium and voltage transients that occur with each cardiomyocyte contraction. We will then fix and immunolabel the cells for atrial and ventricular markers and correlate cell identity to activity on a cell-by-cells basis. This project will enable high throughput, accurate, and cost-effective cardiosafety testing.

Funding agency: NIH/National Heart, Lung, and Blood Institute

Award Date: March 2012

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Project Number: HL086076

Project Title: Live cell and HCS assays to quantify production of cardiomyocytes from stem cells

Project Description:

Cardiomyocytes derived from embryonic stem cells may restore cardiac function in patients suffering from heart failure. This project aims to develop a high content screening system to measure the efficiency of cardiomyocyte production from embryonic stem cells. The system will record intracellular calcium transients, which are a hallmark of differentiated cardiomyocytes. The system will also quantify expression and localization of cardiac-specific structures like myofibrils and proteins like SERCA2. The system will enable testing of candidate compounds for their ability to influence the differentiation of cardiomyocytes for treatment of heart failure.

Funding agency: NIH/National Heart, Lung, and Blood Institute

Award Date: September 2006

Mitochondrial Function

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Project Number: HL105061

Project Title: A New Toxicity Screen to Assess Mitochondrial DNA Content and Protein Synthesis

Project Description:

Many hepato- and cardiotoxic drugs and drug candidates act as mitochondrial toxins. While several assays exist to measure acute mitochondrial toxicity (changes in membrane potential, mitochondrial membrane integrity, and reactive oxygen species generation), few assays can detect long term effects such as mitochondrial DNA depletion and inhibition of mitochondrial protein synthesis. This project aims to develop an automated high content image analysis assay that can identify compounds that deplete mitochondrial DNA and/or proteins (e.g., electron transport chain subunits). Our assay will use automated image analysis to quantify mitochondrial DNA and proteins in fluorescent cell images following compound exposure. We will validate the assay in hepatocyte and cardiac model systems using compounds known to deplete mitochondrial DNA and proteins. Our assay will provide a high throughput, cost-effective solution to screen for long term mitochondrial toxicity in the early stages of drug development.

Funding agency: NIH/National Heart, Lung, and Blood Institute

Award Date: August 2010

Skeletal Muscle

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Project Number: AR073565

Project Title: The Stem Cell-Derived Muscle Function Assay: A High Throughput Screening Platform Utilizing Kinetic Image Cytometry to Discover Therapeutics for Duchenne Muscular Dystrophy

Project Description:

Duchenne Muscular Dystrophy (DMD) is an early onset, progressive, and fatal disease caused by mutations in the DMD gene that prevent expression of the skeletal muscle structural protein dystrophin. This project aims to develop the Stem Cell-derived Muscle Function Assay (SCMFA), an in vitro high throughput screening system for potential DMD therapeutics. The SCMFA will use skeletal muscle differentiated from human pluripotent stem cells from healthy subjects, subjects with DMD, or subjects with Becker Muscular Dystrophy, a milder skeletal muscle condition. We will develop methods to assay the effects of paced contraction and stretching on skeletal muscle function and contractile apparatus biomarker expression. The methods developed for the SCDMFA will apply to other inherited muscular dystrophies and related conditions.

Funding agency: NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases

Award Date: September 2018

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Project Number: AR055604

Project Title: Automated Analysis of Skeletal Muscle Fiber Cross-sectional Area and Metabolic Type

Project Description:

Skeletal muscle morphology provides insight into a wide variety of health issues such as aging, muscle denervation, muscular dystrophy, nutrition, and exercise physiology. This project aims to develop automated image analysis software that can measure the cross-sectional area of muscle fibers in skeletal muscle tissue sections. We will also immunolabel the tissue sections for myosin type I to quantify the percentage of slow twitch fibers within each muscle. The proposed research will generate a high throughput assay that can quantify the effects of experimental interventions in altering muscle physiology and health.

Funding agency: NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases

Award Date: July 2008

Liver

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Project Number: DK082087

Project Title: Automated quantification of lipid droplets in fatty liver tissue sections

Project Description:

Non-alcoholic fatty liver disease results from lipid accumulation in liver cells (hepatocytes) followed by cell damage or death, inflammation, and cirrhosis. This project aims to develop an assay to detect changes in hepatocyte lipid content. We will develop image analysis techniques to quantify the frequency and size of hepatocyte lipid droplets in images of human liver tissue sections. Our assay will enable high content screening for potential therapies for non-alcoholic fatty liver disease and other metabolic conditions.

Funding agency: NIH/National Institute of Diabetes and Digestive and Kidney Diseases

Principal Investigator: Patrick M. McDonough

First Budget Start Date: March 2010

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Project Number: DA026213

Project Title: A High Throughput Imaging Assay for Hepatic Lipid Droplet Formation

Project Description:

 Non-alcoholic fatty liver disease results from lipid accumulation in liver cells (hepatocytes) followed by cell damage or death, inflammation, and cirrhosis. This project aims to develop a high content screening assay to identify compounds that alter hepatic lipid droplet formation in hepatocyte-derived cell lines (murine AML-12 cells and human HuH-7 cells). Our assay will enable discovery of new agents that can treat non-alcoholic fatty liver disease and other metabolic conditions.

Funding agency: NIH/National Institute on Drug Abuse

Award Date: June 2008

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Project Number: DK074333

Project Title: HT Image Assay of Lipid Droplet Formation in Human Adipocytes

Project Description:

Dysregulation of adipocyte differentiation and lipid metabolism can contribute to obesity. This project aims to develop an image-based high content screen to test the effects of drug candidates on the differentiation and metabolic state of cultured human adipocytes. The screen will use image analysis software to quantify the number, size, and distribution of lipid droplets in maturing human adipocytes. The screen will also quantify the expression and distribution of proteins involved in lipid droplet formation and metabolism such as perilipin, adipophilin, and hormone sensitive lipase. Our screen will identify compounds with potential to treat obesity and related conditions like non-alcoholic fatty liver disease, diabetes, and heart disease.

Funding agency: NIH/National Institute of Diabetes and Digestive and Kidney Diseases

Award Date: July 2006

Cancer

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Project Number: MH082378

Project Title: High Throughput Imaging Assay for Beta-Catenin

Project Description:

In normal cells, β-catenin binds transmembrane proteins like cadherins at the plasma membrane. In tumor cells, however, β-catenin moves to the nucleus, where it interacts with transcription factors to increase the expression of proteins that promote mitosis and tumor growth. This project aims to develop an assay to identify compounds that change β-catenin expression and cellular distribution in HeLa cells. The assay will use automated image acquisition and analysis to quantify the amount of β-catenin at the membranes and nuclei of treated cells. The assay will identify potential cancer therapeutics as well as treatments for other conditions that result from β-catenin dysregulation, such as depression and dementia.

Funding agency: NIH/National Institute of Mental Health

First Budget Start Date: August 2007

Pancreas

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Project Number: DK076510

Project Title: Development automated assay-regulators insulin synthesis

Project Description:

Insulin promoter activity is a key indicator of pancreatic beta-cell function. Compounds that stimulate or maintain insulin expression have the potential to preserve and enhance beta-cell function in diabetes. This project aims to develop an automated screen for small molecules that modulate insulin expression in mouse pancreatic MIN6 cells. The system will use automated digital microscopy and image analysis algorithms to measure the expression of a fluorescent reporter under the control of the insulin promoter. This screen can identify potential diabetes therapeutics as well as compounds that inhibit insulin promoter activity and may cause beta-cell dysfunction.

Funding agency: NIH/National Institute of Diabetes and Digestive and Kidney Diseases

Award Date: September 2006