Neurodevelopmental disorders including, intellectual disability, autism spectrum disorder, and schizophrenia inflict 3-5% of the population. Patients suffer from behavioral abnormalities raging from learning deficits to emotional adaptation, such as aggression. Thus far, no mechanism-based therapy exists for these conditions, and all available treatments are palliative. Through the genetics studies over the past decade, dysreguation of chromatin modifications has emerged as a major cause of neurodevelopmental disorders. In particular, enzymes that install or remove methylation of histones, DNA-wrapping proteins, are heavily mutated in neurodevelopmental disorders. Virtually all chromatin modifications are reversible, which opens a therapeutic window of opportunity to restore normal modification level by modulating the Yin-Yang relationship of opposing enzymes. For example, one could inhibit a histone demethylase when the level of a methyl mark is too low within brain chromatin due to the loss of a histone methyltransferase.
Our research team has recently obtained a proof of principle for this “chromatin neutralization” approach using the two mouse models of neurodevelopmental disorders. One is a model of Mental Retardation, X-Linked, Syndromic, Claes-Jensen Type (MRXSCJ), which is caused by the loss of a histone demethylase KDM5C that targets histone H3 lysine 4 methylations (H3K4me). Another mouse model resembles Wiedemann-Steiner syndrome (WSS), which is caused by the loss of KMT2A H3K4 methyl transferase. When we crossed the two mouse lines, cognitive abnormalities and aggression were alleviated. Building upon this promising genetic evidence, our research team is uniquely positioned to test if chemical perturbation of these enzymes can ameliorate the cognitive deficits in mice. Specifically, we will test MM401, a small molecule inhibitor of KMT2A, can reverse the learning impairment, aggression and abnormal H3K4me landscape of KDM5C-knockout mice (MRXSCJ model). A positive outcome of this study will position us to further improve in vivo pharmacokinetics of MM401 and eventually test the compound in human patients. This therapeutic approach may apply not only to MRXSCJ or WSS but also broad neurodevelopmental conditions that involve abnormal chromatin regulation. Our interdisciplinary team consists of following investigators with complementary expertise.
Please Note This Project Is Now Closed.
The Michigan Institute for Clinical & Health Research (MICHR) seeks innovative translational research projects that will ultimately have significant potential to improve patient and community health outcomes. The goal of this funding is to support interdisciplinary research teams in generating sufficient preliminary data to pursue future extramural funding and publication opportunities. We welcome research proposed at any stage of translation, including:
- preclinical research that aims to connect the basic science of disease with human medicine
- clinical research to better understand a disease in humans
- clinical implementation, involving the adoption of interventions demonstrated useful in the research environment into routine clinical care, and
- the study of health outcomes at the population level to determine the effects of diseases and efforts to prevent, diagnose and treat them
MICHR will fund up to five Classic Cubes ($60K) and 13 Mini Cubes ($15K).
No unit or faculty contribution is required.
Project Submission Process
Interested faculty members please provide the following information to be considered for funding:
Click the Comments tab above, and post a project idea in the Mcubed website. Please do not exceed two paragraphs in length. Provide basic details about the proposed research.
Comment should also include:
- Three cube collaborators - faculty names and units. The team must include 3 faculty from at least 2 units, and 1 faculty member on each team must be from Medicine.
- Grant amount requested ($15K or $60K)
- Studies proposing cell or animal models should provide reasoning of how the research will lead to immediate next step studies in humans.
Comments will be accepted until May 15, 2019.
Note: Project duration is one year from the transfer of funds.
For additional questions about this funding opportunity, please contact Beth LaPensee at email@example.com.
For eligibility requirements, use of funds, and details on the application process, please see: