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2013 Pilot Project Award | Overview

Ganesh Mochida, MD

The cerebellum is a part of the brain that controls our motor system to allow precise, coordinated movements. It is also implicated in cognitive functions. Disorders of the cerebellum often present with a severe motor disability and can be accompanied by intellectual disability, thus putting significant burden on the affected individuals and their families. There are many genetic conditions that affect the normal development of the cerebellum, but many of the causative genes remain unidentified.

This proposed research project aims to further our ongoing effort of identifying novel genes that cause malformations of the cerebellum when mutated. We will enroll individuals and families with cerebellar malformations, and sequence their genome using high-throughput DNA sequencing. Once we identify a causative gene mutation, we aim to generate induced pluripotent stem cells (iPSCs) from the affected individual’s blood cells. Despite originating from non-neuronal cells, iPSCs have the capacity to differentiate into neurons, and thus allow us to study neuronal cells from the individuals with a mutation of interest. We propose to study how these cells with a particular mutation proliferate and express different sets of genes, compared to normal cells.

We expect that this study will result in accurate genetic diagnoses in many more children with cerebellar malformations, leading to improved genetic counseling for their families. In addition, we envision an expanded understanding of the biological mechanisms of these disorders, and, ultimately, pathways to novel therapeutic strategies.

Edward Smith, MD

Moyamoya is a rare condition that causes stroke, affecting about 1/1,000,000 people in the US. Major blood vessels, the internal carotid arteries, narrow over time, leading to reduced blood flow to the brain. Ultimately, if untreated, this narrowing results in stroke and death (in 66-90% of patients within 5 years). While surgery can markedly reduce this risk (down to -4%), there are a number of problems that clinicians face that markedly limit their ability to effectively treat patients. First, it can be difficult to detect advanced moyamoya before a stroke occurs. Second, moyamoya is found in several different populations, sometimes alone as the only problem (moyamoya disease) and sometimes in association with other medical conditions (moyamoya syndrome). It is unclear if these different populations manifest varying severity of disease or respond differently to treatments.

Third, the increasing use of brain imaging studies has also led to the situations where the diagnosis of moyamoya is not clear, or when the disease is very early and asymptomatic, making decisions about treatment complicated. Clinicians need better tools to identify when moyamoya is present and to help guide decisions about therapy. This project hypothesizes that there is a common process that is shared by all types of moyamoya - the recruitment and growth of new blood vessels in response to the brain being starved of blood supply- and that this process is regulated by a critical molecule, netrin-1. Netrin-1 is a secreted protein originally discovered in the developing brain, which exerts its effects through a specific panel of effector molecules. We propose that these molecules can be detected noninvasively in the urine and used as biomarkers. Our experiments aim to demonstrate how these urinary biomarkers can be used as a novel method to improve the diagnosis, prognosis and therapy of patients with moyamoya.