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Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: SMALL BUSINESS PHASE II | Award Amount: 900.00K | Year: 2014

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project is the development of a technology to accurately measure small RNA expression. This is an enabling life science research tool. Small RNAs are ubiquitous gene regulators found in the body. Products of the same microRNA gene that vary in length by one or two nucleotides may be involved in a host of diseases, including cancer. The value for developing a method to measure the true profile of microRNAs in a sample would be immense for the research community studying transcriptional regulation, and would open the doors to those interested in drug development and diagnostics. The goal of this proposal is to develop a library preparation kit for non-biased small RNA libraries for Next Generation sequencing. These kits will increase the quality and rate at which global microRNA profiles may be determined for research and clinical applications.

This SBIR Phase II project proposes to develop next generation sequencing technology for small RNA more quantitative and less biased. High throughput sequencing has transformed the landscape of genomic research with its ability to produce gigabases of data in a single run. This has enabled researchers to perform genome wide and high depth sequencing studies that would normally not be possible. Despite this capacity, amplification artifacts introduced during polymerase chain reaction (PCR) assays increase the chance of duplicate reads and uneven distribution of read coverage. Accurate profiling using deep sequencing also has been undermined by biases with over- or under-represented microRNAs. The presence of these biases significantly limits the incredible sensitivity and accuracy made possible by next generation sequencing. The goal of this proposal is to develop novel bias-reducing technology for making small RNA libraries. The proposed kits and protocols will increase the rate at which global microRNA profiles can be determined, and between-sample and within-sample differences (as well as newly discovered small RNAs) can be subsequently validated. This product will result in a major shift in the way small RNA sequencing is performed, and will pave the way for the discovery of new small RNAs.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 292.80K | Year: 2013

DESCRIPTION (provided by applicant): Recent advances in massively parallel cDNA sequencing (RNA-seq) have paved the way for comprehensive analysis of the transcriptome, a set of all RNA molecules including mRNA, rRNA, tRNA and other non-coding RNAs in oneor more populations of cells. RNA-Seq can identify the precise location of transcription boundaries, show how exons are connected and reveal sequence variations in transcribed regions. Taken together, RNA-Seq is the first sequencing based method that allows the entire transciptome to be surveyed in a very high- throughput and quantitative manner, offering both single-base resolution for annotation and digital gene expression levels at the genome scale. However, this technology is under active development and there are several enzymatic steps during library preparation that can contribute to sequence dependent bias, hindering comparisons between genomic regions and adversely affecting transriptome profiling. Ligases used to add on adapter sequences in RNA- Seq have structure based preferences, reverse transcriptases that make the first cDNA strand are prone to copy errors and rearrangements, and polymerases used for amplification often stumble when approaching GC / AT rich regions. The goal of this project isto create a library preparation kit for making minimally biased, highly indexed RNA-Seq libraries for deep sequencing that are constructed in a way to allow transcriptome profiles to be easily and fairly interrogated. Our proposal to develop technology tostudy the transcriptome in an unbiased, high-throughput manner should make future clinical applications a reality and propel research in comparative tissue disease profiles, further un-locking transcriptional regulation. PUBLIC HEALTH RELEVANCEPUBLIC HEALTH RELEVANCE: Advances in massively parallel cDNA sequencing (RNA-Seq) have paved the way for comprehensive analysis of the transcriptome, a set of all RNA molecules including mRNA, rRNA, tRNA and other non-coding RNAs in one or more populationsof cells. Our proposal to develop technology to study the transcriptome in an unbiased and quantitative manner should propel research in comparative tissue disease profiles and further un-lock the diagnostic potential of transcript profiling.


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 750.00K | Year: 2015

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project is the development of a technology to accurately measure small RNA expression. This is an enabling life science research tool. Small RNAs are ubiquitous gene regulators found in the body. Products of the same microRNA gene that vary in length by one or two nucleotides may be involved in a host of diseases, including cancer. The value for developing a method to measure the true profile of microRNAs in a sample would be immense for the research community studying transcriptional regulation, and would open the doors to those interested in drug development and diagnostics. The goal of this proposal is to develop a library preparation kit for non-biased small RNA libraries for Next Generation sequencing. These kits will increase the quality and rate at which global microRNA profiles may be determined for research and clinical applications. This SBIR Phase II project proposes to develop next generation sequencing technology for small RNA more quantitative and less biased. High throughput sequencing has transformed the landscape of genomic research with its ability to produce gigabases of data in a single run. This has enabled researchers to perform genome wide and high depth sequencing studies that would normally not be possible. Despite this capacity, amplification artifacts introduced during polymerase chain reaction (PCR) assays increase the chance of duplicate reads and uneven distribution of read coverage. Accurate profiling using deep sequencing also has been undermined by biases with over- or under-represented microRNAs. The presence of these biases significantly limits the incredible sensitivity and accuracy made possible by next generation sequencing. The goal of this proposal is to develop novel bias-reducing technology for making small RNA libraries. The proposed kits and protocols will increase the rate at which global microRNA profiles can be determined, and between-sample and within-sample differences (as well as newly discovered small RNAs) can be subsequently validated. This product will result in a major shift in the way small RNA sequencing is performed, and will pave the way for the discovery of new small RNAs.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 161.70K | Year: 2013

DESCRIPTION (provided by applicant): Diabetes is a serious, life-threatening disease caused by improper absorption and metabolism of glucose. Increased glucose levels can lead to an accumulation of toxic sugar degradation products, such as methylglyoxal (MG), in the bloodstream. MG is a reactive molecule which can modify and inactivate blood proteins which in turn leads to hypertension, neuropathy, and heart disease. Consequently, MG has been shown to be an excellent biomarker for a number of diabetes-related complications. Unfortunately, all current methods to directly measure MG levels in blood are very expensive, time-consuming and laborious. To fully realize the diagnostic potential of MG, rapid analytical methods are needed for the routine determinationof MG in biomedical samples such as blood. Our proposed Phase I research will create a unique test to measure MG levels in blood samples such as plasma and serum. This unique test will permit researchers to conveniently study the accumulation of reactiveMG in blood before damage to proteins and vasculature has occurred. Our novel assay will use a recombinant bacterial oxidoreductase enzyme (MG-R) capable of specifically and rapidly converting MG into a detectable colorimetric signal in a 96 well plate assay format. To boost sensitivity, we will link our enzymatic detection reaction to an NADP+/NADPH visible colorimetric amplification loop to increase assay sensitivity more than 100-fold. The assay will be optimized and validated using rat and mouse plasmaand serum spiked with known amounts of MG. After validation, we will commercially launch a rapid test kit to directly detect MG in preclinical and other biomedical samples. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Diabetes is a major health threat in the US; this life-threatening disease is rapidly spreading throughout our country (23 million Americans currently affected). Recently, scientists have discovered that a sugar metabolite called methylglyoxal plays a central role in the progression of diabetes - unfortunately there are no methods currently available for routine analysis of methylglyoxal. Our research will create a unique method to rapidly measure methylglyoxal levels in normal and diabetic blood samples; our new analytical method will provide researchers with a critical new diagnostic tool to more-effectively combat diabetes and associated cardiovascular disease.


Grant
Agency: Department of Defense | Branch: Office for Chemical and Biological Defense | Program: SBIR | Phase: Phase I | Award Amount: 150.00K | Year: 2014

Burkholderia pseudomallei and Burkholderia mallei are highly pathogenic Gram-negative bacteria and the causative agents of melioidosis and glanders, respectively. These infections, which occur in humans and other animals, are endemic is wide regions of the developing world. Translational research regarding these pathogens is focused on developing new strategies to detect, treat and ideally protect humans and animals from these infections. In this Phase I SBIR project, we will establish methodologies for the generation of monoclonal antibodies that have high-affinities to Burkholderia antigens. The purpose of these studies is to create new antibody-based prophylactics that can neutralize Burkholderia infections. As a first step, we will isolate carbohydrate antigens from non-pathogenic strains of Burkholderia in forms that will generate appropriate immune responses. We will also assess the relative performance and compatibilities of existing antibodies to bind Burkholderia pathogens, in order to create optimized formulations, which will be assessed for therapeutic benefit in future challenge studies.


Grant
Agency: Department of Defense | Branch: Office for Chemical and Biological Defense | Program: SBIR | Phase: Phase II | Award Amount: 500.00K | Year: 2014

Burkholderia pseudomallei and Burkholderia mallei are highly pathogenic Gram - negative bacteria and the causative agents of melioidosis and glanders, respectively. These infections, which occur in humans and other animals, are endemic is wide regions of the developing world. This Phase II SBIR project will build on the success of our Phase I work, which established methods for generating monoclonal antibodies (MAbs) that bind surface carbohydrates and proteins of these Tier 1 Burkholderia pathogens. In Phase II, MAbs generated with these methods will be screened with a combination of computational, immunological, biophysical, and protection assays. The outcome of Phase II will be a selected subset of MAbs that, based on these assays, have the best functional properties for development as therapeutics. In subsequent phases of this work, the immunological properties and manufacturing capabilities of the MAb subset will be further optimized. The ultimate purpose of these studies is to develop these MAbs for clinical use to neutralize Burkholderia infections in humans.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 225.00K | Year: 2014

DESCRIPTION (provided by applicant): Protein-RNA interactions make a profound contribution to the regulatory logic of post- transcriptional control of gene expression. Tools to decipher this intricate layer of molecular interactions on a global scale are coming to the forefront of molecular biology and genomics. The most wide spread methodology to examine interactions of RNA binding proteins (RBPs) with their targets is an IP-microarray plagued by several experimental pitfalls. The cross-linking immunoprecipitation (CLIP) method overcomes many of these pitfalls while facilitating identification of RNA targets as well as the in situ bindng sites. Developing a novel tool to decipher this intricate layer of molecular interaction is a focusof this proposal. During development, we will identify noise arising from clonal reads and improve the sensitivity of the procedure. Analytical techniques will be developed to allow modeling of ligation efficiency and estimate clonal biases accurately. The ultimate goal of


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 298.94K | Year: 2016

DESCRIPTION provided by applicant DNA methylation has been shown to be associated with cancer inflammatory and metabolic disorders neuronal plasticity and memory formation Up to now DNA methylation has been largely studied by whole genome bisulfite sequencing of populations of cells Studies like the Epigenomics Project and the Genomes Projects have contributed significantly to our understanding of genetic phenotypic and epigenetic variations amongst individuals in a population However all of these studies are essentially averaged snapshots or normalized fixed time assessments of our genetic and epigenetic makeup Nowhere is it more important to study dynamic variation than in epigenomics Almost all our understanding of the epigenome and its regulation has been derived from studies carried out at the population level thousands of cells being sequenced together There is considerable evidence indicating that cell to cell variability in gene expression is ubiquitous even amongst andapos homogeneousandquot populations of cells The extent of epigenetic heterogeneity in diverse cell types in tissues remains largely unknown Our goal in this grant application is to develop a solution to this problem by developing at least two single cell methyl sequencing library preparation protocols that will allow investigators to interrogate epigenetic modifications amongst individual cells of a population PUBLIC HEALTH RELEVANCE DNA methylation has been shown to be associated with cancer inflammatory and metabolic disorders neuronal plasticity and memory formation Up to now DNA methylation has been largely studied by whole genome sequencing populations of cells Our goal is to develop technology that allows for the examination of methylation patterns and stochastic intercellular variation in the epigenomes of single cells


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 270.00K | Year: 2016

DESCRIPTION provided by applicant A key application of deep sequencing is gene expression analysis at the RNA level commonly known as RNA seq Reads from RNA seq cover all regions of an mRNA sequence However sequences derived from the andapos end region are sufficient to indicate gene expression levels All andapos end sequencing methods have revealed that most eukaryotic genes display alternative cleavage and polyadenylation APA where RNA isoforms using different cleavage and polyadenylation sites pAs can be generated from a gene Importantly different APA isoforms have been shown to have different metabolisms including stability localization and translation APA clearly poses a challenge for gene expression analysis Current RNA seq methods cannot capture this information second false pA identification due to internal priming leads to inaccurate APA information third complete analysis of gene expression needs to take into consideration all APA isoforms We have proposed a new method that completely addresses false priming incomplete andapos end annotation and significantly propels research on single cell RNA expression and poly A tail length which have so far been elusive The final goal of this proposal is to develop a commercial kit allowing non specialized labs the ability to examine andapos ends in an accurate and sensitive manner PUBLIC HEALTH RELEVANCE Deep sequencing a k a next generation sequencing technologies have revolutionized biology and medicine in recent years We plan to develop a kit that solves mis priming issues that commonly plague andapos end sequencing methods and provides sensitive and robust analysis of gene expression


Patent
Bioo Scientific Corporation | Date: 2014-05-15

A method and sensor for detecting the presence of specific target nucleic acids uses a biosensor comprising an array of single stranded probe oligonucleotides, wherein one end of each probe oligonucleotide is linked to a label and the other end of each probe oligonucleotide is attached to an electrode of a solid support. The method includes determining the capacitance at one or more of the electrodes, where a change in the capacitance of the one or more electrodes indicates the presence of target nucleic acid complementary to the single stranded oligonucleotide probe.

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