Awarded Grants

Awarded Grants

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An Evaluation of Gene Modification Strategies for Bloom Syndrome

Caroline Kuo

University of California, Los Angeles

$50,000

Awardee: Caroline Kuo

Institution: University of California, Los Angeles

Awarded: $50,000

Funding Period: April 1, 2025 – March 31, 2026

Summary: To date, no studies have assessed the feasibility of gene modification as a potential treatment for Bloom syndrome. This project outlines specific aims that include proof-of-concept experiments essential for evaluating the viability of gene therapy as a therapeutic option for this condition

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The Somatic Mutational Landscape Of Blm-Deficient Tumors: Finding Clues for Future Therapeutic Opportunities

Richarda de Voer

Radboud University Medical Center (Stichting Radboud Fonds)

$150,000

Awardee: Richarda de Voer

Institution: Radboud University Medical Center (Stichting Radboud Fonds)

Awarded: $150,000

Funding Period: April 1, 2025 – March 31, 2027

Summary: Despite cancer surveillance strategies >80% of individuals with Bloom syndrome (BSyn) will have developed a malignancy by the age of 40 years. Treatment of malignancies in individuals with BS is still mostly based on standard-of-care treatments. With this proposal we aim to unravel the (mutational) mechanisms responsible for tumor initiation and progression in individuals with BSyn. We expect to gain insights into the processes relevant for tumor development in individuals with BSyn, leading to clues for future therapeutic opportunities. We will repurpose archived tumors from individuals with BSyn to:

1. Perform whole-exome or whole-genome sequencing to determine the somatic single base and small indel mutation landscape, investigate mutational signatures of defective DNA repair, mutated driver genes and identify potential signs of homologous recombination deficiency (HRD);

2. Explore the immune landscape of tumors using multiplex immunohistochemistry.

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Novel Approaches to Cancer Surveillance in Bloom Syndrome

Vivian Chang

University of California, Los Angeles

$150,000

Awardee: Vivian Chang

Institution: University of California, Los Angeles

Awarded: $150,000

Funding Period: April 1, 2025 – March 31, 2027

Summary: There is a general lack of data on effective cancer surveillance in most rare cancer predisposition disorders and this remains a challenge for patients with Bloom syndrome as well. A landmark study of patients with a different rare cancer predisposition disorder known as Li-Fraumeni Syndrome caused by germline TP53 variants showed that biochemical and imaging surveillance is feasible and associated with improved long-term survival. Standard cancer surveillance approaches though have limitations, including expense and invasiveness, leading to decreased compliance. Emerging technologies that enable longitudinal “liquid biopsies” have shown significant promise to detect cancer through peripheral blood sampling. The long-term goal of this project is to establish an international collaboration with sharing of biospecimens and data across borders in order to develop, validate, and test effectiveness of novel, minimally invasive cancer surveillance methods.

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Model systems to study the Bloom Syndrome Helicase in Homologous Recombination

Roger Greenberg

University of Pennsylvania

$100,000

Awardee: Roger Greenberg

Institution: University of Pennsylvania

Awarded: $100,000

Funding Period: September 1, 2022 - August 31, 2024

Project Summary:

Bloom Syndrome arises due to inherited mutations in the gene that encodes the BLM helicase. Patient cells experience myriad alterations to their DNA due to deficiency in specific aspects of a DNA repair process known as homologous recombination. We have developed systems that allow us to identify the function of the BLM helicase in DNA repair at a defined region of the human genome. We have used these approaches to publish high impact papers during this funding period that describe the role of BLM in DNA repair. In year two of this project, we expect to gain a better understanding of how BLM helicase acts to direct DNA repair and strategies to bypass the need for BLM when mutations in the BLM gene arise.

Publications:

Zhang T, Rawal Y, Jiang H, Kwon Y, Sung P, and Greenberg RA. Break Induced Replication Orchestrates resection dependent template switch. Nature 619(7968):201-208, 2023.

Jiang H, Zhang T, Kaur H, Shi T, Krishnan A, Kwon Y, Sung P, and Greenberg RA. BLM helicase unwinds lagging strand substrates to assemble the ALT telomere damage response. Molecular Cell 84(9):1684-98, 2024.

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Spatial profiling of scRNAseq signatures in human parathyroid glands

Julie Ann Sosa

University of California at San Francisco

$50,000

Awardee: Julie Ann Sosa

Institution: University of California at San Francisco

Grant Amount: $50,000

Funding Period: April 1, 2021 - March 31, 2022

The objectives of this project were to: (1) utilize transcriptomic methods to define individual cell types within the human parathyroid, and (2) employ digital spatial profiling to visualize the localization of these cell types within the native parathyroid gland architecture. The developmental pilot phase work supported by the grant enabled us to establish a solid foundation of procedural optimization and proof of concept data for scaling our single cell sequencing efforts to a larger, more broadly representative cohort of donor parathyroid glands. 

 

The scientific objectives completed during the one-year project period are essential for comprehensive mapping of the human parathyroid gland.  The specific landmarks achieved include: demonstration that our live organ procurement work flow preserves tissue viability and maintains intact biochemical function; validation of recovery efficiency, parathyroid marker expression and cellular integrity in suspension; comparative assessment of whole cell vs nuclear isolation for downstream molecular analysis; validation of a novel split-pool sequencing approach that greatly improves capture efficiency, reduces selective recovery bias, and eliminates library construction batch effect concerns; digital spatial profiling of archived normal parathyroid gland sections to demonstrate the capture and whole transcriptome interrogation of specific cellular subsets demarcated by marker gene expression; and the molecular data from these studies showing that the cellular composition and transcriptional profiles of parathyroid gland tissue are dynamic rather than static.  This last finding reveals that the cellular content and biochemical activity of the parathyroid gland may be physiologically conditional, suggesting that functional reconstitution of the parathyroid gland is not a fixed target, but instead requires complementation of adaptive capacity in addition to terminally differentiated cellular phenotypes.  These key data will inform future and ongoing studies to reconstitute native parathyroid gland function.

Publication:

Digital spatial profiling of human parathyroid tumors reveals cellular and molecular alterations linked to vitamin D deficiency

Chia-Ling Tu, Wenhan Chang, Julie A Sosa, James Koh

PNAS Nexus, Volume 2, Issue 3, March 2023, pgad073

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Nucleic acid binding by ZC4H2

Daniel Dominguez, PhD

UNC at Chapel Hill

$50,000

Awardee: Daniel Dominguez, PhD

Institution: UNC at Chapel Hill

Award Amount: $50,000

Funding Period: January 1, 2021 - December 31, 2021

Summary:

Mutations or genetic rearrangements in the protein, ZC4H2, cause a group of X-linked neurodevelopmental disorders for which there are no treatments. While the importance of this protein is clear, the specific function of ZC4H2 is still unknown. ZC4H2 is predicted to be a zinc-finger protein. We hypothesize that like many other zinc-finger proteins, ZC4H2 directly binds DNA or RNA, and functions to regulate gene expression programs required for normal development. Our goal is to determine if ZC4H2 interacts with nucleic acids and to identify specific genes and/or gene expression pathways that become dysfunctional when ZC4H2 is mutated. Patients suffering from ZC4H2-associated rare disorders have little recourse; understanding the biological function of this protein is a critical and necessary first step to uncover potential therapeutic approaches. 

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A working prototype of an in-home ionized calcium monitoring device using a paper-based ion-selective optode and an optical reader

Xuewei Wang, PhD

Virginia Commonwealth University

$149,019

Awardee: Xuewei Wang, PhD

Institution: Virginia Commonwealth University

Award Amount: $149,019

Funding Period: January 1, 2020 - December 31, 2020

Project Summary:

We are developing test strips for ionized calcium in finger-prick blood samples. One drop of blood can be easily introduced into the strip by patients. The optical response of the strip is recorded by a regular smartphone equipped with a customized app. The test can be finished within two minutes because of the fast sensor response. The concentration of ionized calcium can be accurately determined in a range of 0.1 to 5.0 mmol/L (0.4 to 20.0 mg/dL). There is no interference from other molecules and ions in the blood. Therefore, this new technology will enable the in-home measurement of calcium in the blood and allows the management of hypoparathyroidism by the patient themselves.

Final Summary:

Affordable and portable blood calcium sensors using a smartphone detector have been developed. These sensors empower patients to measure their calcium ion concentration at home using blood collected by fingerstick.

Publications:

R. Wang, X. Wang. Sensing of inorganic ions in microfluidic devices. Sensors and Actuators B: Chemical 2021, 329, 129171

R. Wang, Y. Zhou, N. Ghanbari Ghalehjoughi, Y. Mawaldi, X. Wang. Ion-Induced Phase Transfer of Cationic Dyes for Fluorescence-Based Electrolyte Sensing in Droplet Microfluidics. Analytical Chemistry, 2021

N. Ghanbari Ghalehjoughi, R. Wang, S. Kelley, X. Wang. Ultrasensitive Ionophore-Based Liquid Sensors for Colorimetric Ion Measurements in Blood. Analytical Chemistry, 2023, 95, 12564-12564

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Developing human pluripotent stem cells for investigation and treatment of hypoparathyroidism

Rene Maehr, PhD

Umass Medical School

$500,000

Awardee: Rene Maehr, PhD

Institution: Umass Medical School

Award Amount: $500,000

Funding Period: January 1, 2020 -December 31, 2020

Summary:

The parathyroid gland is critically involved in regulation of calcium homeostasis of the body. Hypoparathyroidism as encountered by parathyroid damage, hypoplasia, or as a result of thyroid and parathyroid surgery, results in chronic hypocalcemia and low-turnover bone disease. Human pluripotent stem cells could provide a virtually unlimited source of parathyroid-like cells with calcium level responsiveness, offering a unique opportunity for development of a cell replacement products capable of regulating calcium levels. To unlock human pluripotent stem cell-based treatment strategies, robust and safe stem cell differentiation protocols need to be established. Here, we propose to develop an approach that is based on human pluripotent stem cell differentiation according to a developmental roadmap, and cutting edge humanized mouse avatar models for functional evaluation of human parathyroid-like cells. We expect this rigorous approach to provide several high-impact resources, including a source of high-fidelity human parathyroid-like cells and novel mouse models for studying parathyroid function.

Publication:

Integration of single-cell transcriptomes and chromatin landscapes reveals regulatory programs driving pharyngeal organ development - Nature Communitcations

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