Awarded Grants

Awarded Grants

MDBR, Pitt Hopkins Million Dollar Bike Ride MDBR, Pitt Hopkins Million Dollar Bike Ride

Tcf4 in gut development; investigating underlying causes of gastro-intestinal problems in patients with Pitt Hopkins syndrome

Simone Mesman

University of Amsterdam

$58,602

Awardee: Simone Mesman

Institution: University of Amsterdam

Grant Amount: $58,602

Funding Period: February 1, 2025 - January 31, 2026

Summary:

Many patients with Pitt Hopkins syndrome (PTHS) experience serious gastro-intestinal (GI) problems, like severe abdominal bloating and constipation. Recently, two patients in the Netherlands unexpectedly passed away due to GI complications, underlining the need to thoroughly understand these problems in order to develop better treatment. Although these GI problems have a large influence on the quality of life of patients with PTHS and their caregivers, very little research has been done to determine the underlying causes of these problems. With the current project we aim to shed light on the possible cause(s) of the the GI problems and possible therapeutic strategies to alleviate (some of) these problems. To this end we will investigate the role of Tcf4 in gut development in patients with PTHS and in specific mouse models carrying Tcf4 mutations. To determine whether Tcf4 functions in the gut or in gut development, we will examine the normal expression pattern of Tcf4 in the human and murine gut. Next to this we will investigate the cellular and molecular architecture of the gut in patients with PTHS and mice carrying specific Tcf4 mutations. Furthermore, we will study co-morbidity of GI problems with other PTHS symptoms to determine whether specific symptoms may be related to each other. Taken together, the results from this study will help us identify the underlying causes of GI problems in patients with PTHS and pinpoint possible therapeutic targets. Furthermore, it will help us fine-tune existing treatments specifically aimed to alleviate GI problems in PTHS.

Read More
MDBR, Pitt Hopkins Million Dollar Bike Ride MDBR, Pitt Hopkins Million Dollar Bike Ride

Identification of vulnerable cell types and quantification of cell type-specific differential gene expression in the Pitt-Hopkins Syndrome mouse model

Brady Maher

Johns Hopkins University School of Medicine

$73,473.00

Awardee: Brady Maher

Institution: Johns Hopkins University School of Medicine

Grant Amount: $73,473.00

Funding Period: February 1, 2024 - January 31, 2025

Summary:

The brain is composed of two major cell types, neurons and glia; however, these two cell classes quickly become very complex as you begin to categorize them into specific subtypes of cells based on their structure and function. For instance, glia cells are comprised of astrocytes, oligodendrocytes, and microglia, which all have unique structures and functions, and these three cell types can be further divided into additional subtypes. This complexity is even greater for neurons, which are first subdivided into excitatory and inhibitory neurons, but then have so many subtypes they cannot all be listed here. Recent technological advances in single cell sequencing (scRNAseq) have emerged that allow us to quantify the expression of genes within individual cell types, which is critically important because each subtype of cell expresses different genes that regulate the specific function of that cell type. Transcription factor 4 (Tcf4), is a transcription factor that regulates expression of specific genes, however the set of genes it regulates, differs depending on the cell type. Currently, there is no data available that describes how disease-causing mutations in TCF4 effects cell type specific expression in the brain. Therefore, we propose to perform scRNAseq on brain samples from the PTHS mouse model and WT littermates. Previous results from our lab and others have shown that Tcf4 is highly expressed during brain development and mutations in Tcf4 result in alterations in the proportions of specific types of cells (e.g., GABAergic interneurons and oligodendrocytes), however we hypothesize this list of vulnerable cell types is not complete. In addition, Tcf4 is expressed throughout the lifespan, where it is continually regulating gene expression in a cell-type dependent manner. Unfortunately, the field currently lacks an understanding of which sets of genes Tcf4 regulates in any specific cell type. Our proposal is designed to fill in these important knowledge gaps and will help to confirm prior observed vulnerable cell types and identify new cell types of risk. In addition, our approach will identify genes that are differentially expressed in specific cell types, which will help to identify genes that can be targeted by cell type-specific therapeutic approaches. We plan to openly share our results with the research community. We believe it will be beneficial to improving emerging gene therapy approaches by informing us about which cell types should be modified. We believe it will serve to identify vulnerable cell types that may in the future be replaced using cell replacement therapies. Lastly, we believe these datasets will be useful for computational approaches that are using artificial intelligence and machine learning paradigms to identify therapeutic targets and predict effective therapeutic compounds.

Read More
MDBR, Pitt Hopkins Million Dollar Bike Ride MDBR, Pitt Hopkins Million Dollar Bike Ride

Development of proof-of-concept Pitt-Hopkins Syndrome therapy by upregulation of TCF4 transcriptional activity

Tonis Timmusk

Tallinn University of Technology

$71,650.00

Awardee: Tonis Timmusk

Institution: Tallinn University of Technology

Grant Amount: $71,650.00

Funding Period: February 1, 2023 - January 31, 2024

Summary:

Pitt Hopkins syndrome (PTHS) is a genetic developmental disorder that severely affects cognitive, motor and social development. PTHS has been diagnosed in less than 1000 people in the world. It is caused by mutations in one of the two alleles of a gene called TCF4, which encodes a protein named Transcription Factor 4. Most of the mutations found in TCF4 gene in PTHS patients are of de novo origin meaning that the mutation is not present in the parents. TCF4, as other transcription factors, is a protein that regulates the expression of genes. In the nervous system TCF4 plays an important role in proliferation, differentiation and migration of neurons, as well as brain plasticity. Upregulation of the transcriptional activity of the functional TCF4 protein could improve the symptoms of PTHS. The goal of the current project is to develop a method to upregulate TCF4 activity levels by targeting TCF4 co-regulators.

Read More
MDBR, Pitt Hopkins Million Dollar Bike Ride MDBR, Pitt Hopkins Million Dollar Bike Ride

Rescuing oligodendrogenesis and myelination as possible treatment for Pitt-Hopkins patients

Simone Mesman

Swammerdam Institute of Life Sciences, University of Amsterdam

$78,530

Awardee: Simone Mesman

Institution: Swammerdam Institute of Life Sciences, University of Amsterdam

Grant Amount: $78,530

Funding Period: February 1, 2022 - January 31, 2023

Summary:

In the brain of Pitt-Hopkins patients myelination, fatty sheets surrounding axons of neurons, is affected. The correct construction of these myelin sheets is crucial for proper brain functioning and neuronal communication. Incorrect myelination generally results in affected brain functioning and could be an underlying cause for defects in brain functioning as detected in PTHS. We propose to study myelination under inflence of PTHS-related Tcf4 mutations, by investigating myelination profiles in PTHS patients and by studying the effects of these mutations on oligodendrogenesis, the generation of oligodendrocytes the cell-type that produces myelin.

Read More