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The Jackson Laboratory Center for Precision Genetics Advances Therapeutics for Rare Diseases

Enabled by ongoing advancements in genome editing technology, precision disease modeling is an increasingly important component of personalized medicine approaches to treat human disease. In 2014, ORIP at NIH launched the Precision Disease Modeling Initiative (PAR-14-280) and funded three U54 Pilot Disease Modeling Centers in 2015.

Zebrafish Community Cre/lox Resource

Zebrafish Community Cre/lox Resource

Grant Numbers: R24OD020166 and R24OD036201


Research Emphasis/Objectives Zebrafish embryo

The mission of the Zebrafish Community Cre/lox Resource (CCR) is to provide the zebrafish community with Cre resources that open new areas of investigation and promote novel discoveries in human health, development, and disease. With CRISPR/Cas9 precision targeted integration, the Zebrafish CCR can generate Cre knock-ins and floxed alleles in any gene of interest, unlocking previously inaccessible cell lineages and cell typespecific gene studies to broaden the scope and impact of zebrafish research.

Current Research

The Zebrafish CCR provides precision Cre and tamoxifen regulated-CreERT2 knock-ins for spatial and temporal analysis of proneural, mesoderm, endoderm, vascular, blood, and hematopoietic stem cell lineages. The resource is building a set of UFlip Floxed conditional alleles in genes that regulate the epigenome and mitochondrial function, rapidly emerging areas crucial to development, disease, and regeneration. Floxed alleles allow simultaneous gene inactivation and mRFP labeling of mutant cells.

Zebrafish embryo Services Provided

The Zebrafish CCR currently has 10 Cre/CreERT2 lines for proneural, mesoderm, endoderm, vascular, and hematopoietic stem cell lineages. Three floxed lines are available for cell cycle control and Hdac1-mediated epigenetic regulation of gene expression. The resource has seven floxed lines in progress for histone and DNA methylation regulation, and one floxed line for the nuclear encoded mitochondrial DNA replicase PolG. The resource is regularly updated as new lines become available. Requests for lines are made online through the Zebrafish CCR website.

Contact Information

3005 Advanced Teaching and Research Building
2213 Pammel Drive
Iowa State University
Ames, IA 50011-1101
515-294-4445
[email protected]

Principal Investigator

Maura McGrail
[email protected]

Additional Contact

Jeffrey J. Essner
[email protected]

Profile of a Veterinary Scientist: Rachael Wolters, D.V.M., Ph.D.

Respiratory viruses—including SARS-CoV-2 and influenza—have affected public health significantly in recent years. Dr. Rachael Wolters, a recent graduate of the Ph.D. program at the Vanderbilt Vaccine Center at Vanderbilt University, studies how to use antibodies to protect infants from viral diseases, such as influenza and HIV. Dr. Wolters is the recipient of an ORIP Special Emphasis Research Career Award (SERCA) K01 (K01OD036063), which helped her find her path to an independent faculty position.

Baylor College of Medicine U54 Program Seeks to End the Diagnostic Odyssey for Patients with Rare Diseases

With the introduction of new techniques in molecular biology—such as clinical exome sequencing, whole-genome sequencing, RNA sequencing, and metabolomics—researchers are equipped with more tools than ever to understand the genetic basis of diseases that affect human health. This ongoing discovery of novel disease genes has paved the way for structural, functional, and mechanistic insights, facilitating personalized approaches to disease management.

Transgenic RNAi Project (TRiP) Platform at the DRSC/TRiP Functional Genomics Resources

Grant Numbers: R24OD030002, R24OD031952, R24OD035556


Research Emphasis/Objectives

Fly wing.

The Transgenic RNAi Project (TRiP) is an in vivo functional genetics platform that has generated more than 20,000 short hairpin RNAs (shRNA) and single-guide RNAs (sgRNA) fly stocks for the research community. These resources, which are distributed by the Bloomington Drosophila Stock Center (BDSC), provide powerful, versatile, and transformative tools for gene knockdown, knockout, and activation. Researchers have used these fly stocks extensively to model human diseases associated with altered gene expression.

Current Research

The study design. To complement the shRNA and sgRNA collections, new in vivo resources were generated to support three aims. First, the resources enabled combinatorial studies using multiple binary expression systems to study signaling between different tissues and cell types. Focusing on genes with well-characterized GAL4 expression patterns, a set of more than 40 tissue-specific LexA-GAD and QF2 insertions by CRISPR knock-in were generated. Second, the resource enabled the validation of scRNA gene clusters using split-Gal4 lines. Using an algorithm that determines the smallest unique set of marker genes that define a cluster, several hundred highly specific Gal80-repressible split-Gal4 knock-in lines were generated. Last, the resource supported the detection of fly proteins through the insertion of a NanoTag epitope at the C-terminus of more than 300 high-confidence Drosophila orthologs of human mitochondrial disease genes that can then be recognized by an existing high-affinity nanobody against the NanoTag. Together, these new in vivo resources will dramatically expand the scope of reagents available to researchers who are using the fly model to understand the etiology of human diseases.

Services Provided

The TRiP supports the production of fly stocks with shRNAs for gene knockdown; sgRNAs targeting gene-coding sequence for gene knockout; sgRNAs targeting upstream gene regions, such that they are useful for CRISPR overexpression; and CRISPR knock-in lines for LexA/QF, Split-Gal4, and endogenous epitope tags. Immediately following production and validation, the fly stocks are shared with the BDSC for distribution to the community.

Contact Information

Jonathan Zirin, Ph.D.
Assistant Director of DRSC/TRiP Functional Genomics Resources
Harvard Medical School
New Research Building, Room 336
77 Avenue Louis Pasteur
Boston, MA 02115
Email: [email protected]

Principal Investigator

Norbert Perrimon
Harvard Medical School
Phone: 617-432-7672
Email: [email protected]

Fourteenth Comparative Medicine Resource Directors Meeting: Advancing Biomedical Research—Integrative Approaches and Innovations

The biennial Comparative Medicine Resource Directors (CMRD) Meeting is intended to provide a forum for exchange of new information, advances, and ideas; facilitate the development of synergistic working groups, interactions, and collaborations among resources, as well as with National Institutes of Health (NIH) institutes, centers, and offices; and offer opportunities for sharing experiences, strategies, and best practices to optimize access, use, and administration of resources. The fourteenth CMRD Meeting was held August 6 and 7, 2024.

Zebrafish Embryo and Larvae Cryopreservation Resources

Grant Number: R24OD034189


Research Emphasis/Objectives

The study design

Zebrafish models are invaluable tools for understanding human health and disease and have taught us much of what we know about biology. Immense efforts have gone into the generation of transgenic, reporter, and mutant lines; however, maintaining live fish indefinitely has become a huge cost burden that also puts animals at risk. A laboratory at the Center for Engineering in Medicine & Surgery is using nature-inspired cryopreservation methods to increase the hypothermia tolerance of zebrafish embryos and larvae for long-term biobanking.

Services Provided

The laboratory is advancing cryopreservation techniques by systematically optimizing methods for introducing cryoprotective agents into zebrafish embryos and larvae. This approach merges established practices with innovative strategies to enhance preservation efficacy and cellular viability, ensuring the preservation of valuable transgenic lines and disease models for future research applications.

Contact Information

Center for Engineering in Medicine & Surgery
51 Blossom Street
Boston, MA 02114

Principal Investigator

Shannon N. Tessier, Ph.D. 
Associate Professor, Harvard Medical School
Director of Surgical Research, Massachusetts General Hospital
Center for Engineering in Medicine & Surgery 
Email: [email protected]
Website: https://www.massgeneral.org/surgery/cems/faculty-and-staff/shannon-tessier

Additional Contact(s)

Rasha Al-attar, Ph.D.
Research Fellow
Email: [email protected]

Trisomy 21 Model Atlas

Grant Number: R24OD035579


Research Emphasis/Objectives

An illustration of a mouse. Trisomy 21 Model Atlas.

Down syndrome—also called trisomy 21 (T21)—is a genetic condition caused by the presence of an extra copy of chromosome 21. T21 is the most prevalent chromosomal abnormality and a leading cause of intellectual and developmental disability. T21 affects the development and/or function of nearly every organ system, predisposing individuals with T21 to many co-occurring conditions, including Alzheimer’s disease, congenital heart defects, and autoimmune disorders. Although it is known that T21 causes genome-wide dysregulation of gene expression programs, little is known about how T21 affects gene expression across different tissues and organs and how these effects contribute to the etiology of the co-occurring conditions of T21.

The study design.

The main goals of the Trisomy 21 Model Atlas are to (1) generate a data resource containing tissue-specific murine and human transcriptomes matched to histopathology and (2) share the data through an open access researcher portal.

Current Research

The Trisomy 21 Model Atlas currently is in the data generation phase.

Contact Information

Principal Investigator

Matthew Galbraith, Ph.D.
Linda Crnic Institute for Down Syndrome
University of Colorado Anschutz Medical Campus
Aurora, CO
Email: [email protected]

Additional Contact(s)

Kelly Sullivan, Ph.D. 
Email: [email protected]

Joaquin Espinosa, Ph.D.
Email: [email protected]

Squirrel Monkey Breeding and Research Resource

Grant Number: P40OD010938


Research Emphasis/Objectives

Front gate sign. The University of Texas. MD Anderson Cancer Center. Making Cancer History, Michale E. Keeling Center for Comparative Medicine and Research.

The Squirrel Monkey Breeding and Research Resource (SMBRR) is a unique national resource that supports research aimed at better understanding the biology of the squirrel monkey, thereby enhancing its value in biomedical research. The SMBRR provides animals, tissues and biological fluids, cell lines, expert advice, and other research resources to NIH-funded grantees.

Current Research

Squirrel monkeys are used in a variety of NIH-supported research programs, including those focused on infectious disease, aging, immune therapies in the treatment of Alzheimer’s disease and related dementias, neuroscience, vision, drug addiction, and substance use.

Services Provided

Preclinical and Regulatory Studies

The Preclinical Studies Program at the Keeling Center for Comparative Medicine and Research serves MD Anderson and other investigators who are developing novel therapeutics and require Good Laboratory Practice (GLP)–compliant toxicology and safety studies to support Investigational New Drug applications to the U.S. Food and Drug Administration (FDA) so that testing in human clinical trials can begin. More than 50 faculty and staff certified in their respective specialty areas from across the Keeling Center support the program. The Keeling Center’s laboratories, animal facilities, and clinical veterinary components are validated for GLPs and have been inspected/audited numerous times by the FDA and outside study sponsors. The laboratories are compliant with the Code of Federal Regulations, 21 CFR Parts 58 and 11. An independent, onsite Quality Assurance Unit reporting directly to the Director of the Keeling Center monitors the program and each individual GLP study. 

Anatomic Pathology Services

The Anatomic Pathology Section provides comprehensive diagnostic, collaborative, and research-related pathology services and a tissue/biological fluids banking program. Capabilities include necropsy and histopathology services. In addition, the section conducts FDA-regulated, GLP-compliant nonclinical studies in support of cancer drug development. The staff consists of three board-certified veterinary anatomic pathologists and three certified histotechnologists.

Diagnostic Laboratory Services

The diagnostic laboratory provides traditional laboratory services in the areas of hematology, coagulation, clinical chemistry, microbiology, serology, parasitology, and molecular diagnostics (PCR). The support staff consists of seven medical professionals: five medical technologists (four of whom are certified by the American Society of Clinical Pathologists) and one American Association for Laboratory Animal Science Laboratory Animal Technologist–certified animal resources technologist who supports tissue and biological fluid collection and banking. The clinical pathology laboratory is a validated, GLP-compliant facility; has been inspected by the FDA; and is frequently audited by outside study sponsors. All laboratory services are conducted under the supervision of a veterinary clinical pathologist.

Biological Resources

The Keeling Center is a longtime provider of biological and in vitro products to state and federal government institutions and contract research organizations, as well as diagnostic and academic facilities. The Center specializes in animal whole blood, plasma, serum, tissues, and other products that may be required for clinical testing and research diagnostics. It works to tailor the collection of biological matrices to meet its customers’ needs, including anticoagulant selection, donor population identification, matrix collection protocols, and diagnostic testing. In addition to blood products, other biological materials and tissues may be obtained as requested.

Clinical Laboratory Services

The Keeling Center offers a complete range of clinical pathology laboratory services to support research animal models, discovery research, preclinical studies, and/or clinical trials. Its clinical pathology laboratory is staffed by both registered clinical laboratory scientists and laboratory animal specialists with extensive knowledge of animal and human clinical laboratory services. The Center’s state-of-the-art laboratory can support all stages of human and veterinary drug development, and it conducts testing in accordance with the current standards for GLPs.

Infectious Disease Services

The Keeling Center utilizes a wide variety of animal models in its drug discovery and preclinical research programs. Its Infectious Disease Testing Services are built upon a foundation of contamination prevention measures, effective pathogen detection, and scientific and technical proficiency. The cornerstone of this service is a diagnostic laboratory that delivers sensitive and specific testing to screen animal facilities, research biologics, and a range of research animal models, including mice, rats, and nonhuman primate species.

For more information, please review ORIP’s Nonhuman Primate Resources fact sheet.  

Contact Information

William D. Hopkins, Ph.D. 
Professor
Keeling Center for Comparative Medicine and Research at The University of Texas MD Anderson Cancer Center
650 Cool Water Drive
Bastrop, TX 78602
Phone: 512-332-7543
Email: [email protected]

Principal Investigator

William D. Hopkins, Ph.D.
Professor
Keeling Center for Comparative Medicine and Research at The University of Texas MD Anderson Cancer Center
650 Cool Water Drive
Bastrop, TX 78602
Phone: 512-332-7543
Email: [email protected]

Center Director

William D. Hopkins, Ph.D.
Professor
Keeling Center for Comparative Medicine and Research at The University of Texas MD Anderson Cancer Center
650 Cool Water Drive
Bastrop, TX 78602
Phone: 512-332-7543
Email: [email protected]

Additional Contact(s)

Elizabeth Lindemann
Keeling Center for Comparative Medicine and Research at The University of Texas MD Anderson Cancer Center
650 Cool Water Drive
Bastrop, TX 78602
Phone: 512-332-5209
Email: [email protected]

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