Patrizia Casaccia, MD, PhD

Casaccia Laboratory, Epigenetics of Neural Repair

Four Research Areas:

1. Epigenetic Regulation of Gene Expression

2. Developmental Neurobiology

3. Translational Research (Drug Discovery for Myelin Repair and preservation of Axonal function) 

4. Personalized Medicine of Demyelinating Disorders

Oligodendrocytes are the myelin-forming cells of the CNS and are essential for proper functioning of neural circuits. These cells are damaged by a wide variety of stimuli, ranging from prematurity in babies to ischemic or immunological attacks in adult brains (i.e. Multiple Sclerosis). Using mouse and rat models, chromatin immunoprecipitation, proteomics, and genome-wide screens we are defining the mechanisms responsible for the differentiation of multipotential progenitors and neural stem cells into myelin-forming cells.  The goal of these studies is to understand how myelin-forming cells are generated during normal development in order to better understand mechanisms of de-regulated differentiation (i.e. cancer) and to design therapies for repairing aberrant or defective formation of oligodendrocytes in children (i.e. Canavan disease, etc.) and demyelination caused by stroke, inflammatory demyelination, spinal cord injury or trauma, in the adult brain.
 
Project #1: Epigenetic Regulation of Gene Expression

Even though they all have the same DNA, each cell type expresses a set of specific genes and retains a precise “MOLECULAR MEMORY” of cell identity. This area of research in the lab is aimed to answering the following questions:

- How do distinct cells acquire their UNIQUE identity within an organism? (How does an oligodendrocyte “know to make myelin” rather than producing digestive enzymes?)

- What are the mechanisms that allow stability and homeostasis?

- Does AGE, or disease alter the mechanism regulating cell identity ?

Project #2: Developmental Neurobiology

How does a progenitor decide to become an oligodendrocyte ? What happens to the nuclear architecture during this transition? What is the relationship between proliferation and differentiation? Are progenitors intrinsically “biased” towards a myelinating or non-myelinating phenotype? Can this bias be modulated by the environment?

Project #3. Repair of Demyelinated Lesions

Multiple sclerosis is a disease characterized by clinical symptoms that are consequent to myelin damage.  Recovery of function can be obtained only after progenitors differentiate into myelinating oligodendrocytes and form new myelin. Because the clinical course of demyelinating diseases results from a disequilibrium between damage and repair we are tackling the problem from both ends: reduce damage and enhance repair by developing new drugs.   In collaboration with the group of Chemical Epigenomics at Mount Sinai, we are screening newly synthesized pharmacological compounds in brain cells  from rodents and humans, for their ability to form new myelin. The most promising molecules are then tested inmice for the ability to enhance recovery from experimentally induced demyelination.

Project #4. Personalized Medicine of Demyelinating Disorders

The overall idea that we are testing, in collaboration with the Corinne Goldsmith Center for Multiple Sclerosis is that each patient has a unique “signature” which results from the interplay of genes, environment, gender and age.  We believe that this signature modulates the course of the disease and the response to therapy and can be identified by analyzing DNA and RNA from MS patients, by adopting molecular and cellular techniques.

For each patient we want to create a “personalized” disease-model in a dish, using the latest induced Pluripotent Stem Cell technology.

Once this model is established, hundreds of commercially available and newly synthesized pharmacological agents can be screened using robotic technology, to define novel personalized strategies that will decrease disability and enhance repair.