A gift from Leonard and Isabelle Goldenson was made in recognition of their long and close partnership with Dr. William Berenberg, in working to defeat cerebral palsy, to establish the Leonard and Isabelle Goldenson Research Fellowship Fund. The Fund was established to support basic and/or clinical research, which is clearly relevant to the causes, prevention, and treatment of cerebral palsy at Harvard Medical School and/or its affiliated institutions.
Current Projects:
Ayal Ben-Zvi, Ph.D.
Postdoctoral Fellow, Chenghua Gu Lab
Harvard Medical School
It is estimated that about 70% of CP cases originate prenatally. Deficits in brain oxygen during embryonic development could progress into cerebral lesions. Indeed, a major feature in CP etiology is abnormal blood supply to the brain. However, a lack of fundamental understanding of the factors and genes governing the vessel/neural architectural relationship in the brain hampers the development of diagnostic tools for the prevention of CP. In this project we will identify and characterize molecular components used to establish and maintain neurovascular interactions in the brain during development. We will use a mouse model to visualize the interaction between neurons and blood vessels in the developing brain. These observations will guide us in identifying molecules responsible for normal development of brain vasculature. The proposed research will contribute to the understanding of the developmental neurovascular cross-talk that allows for proper physiology of the mammalian brain. Finally, it could provide insights into the mechanisms underlying the perinatal cerebral ischemia that leads to CP.
Tony del Rio, Ph.D.
Postdoctoral Fellow, Lisa Goodrich Lab
Harvard Medical School
The precise spatial and temporal regulation of cell signaling activity is critical throughout nervous system development. Cell signaling is frequently controlled by tyrosine phosphorylation, a modification that alters protein activity. Many aspects of neural development depend on receptor tyrosine kinases (RTKs), a diverse class of proteins that catalyze tyrosine phosphorylation. RTK activity itself is precisely modulated by a variety of regulatory systems. One of the most recently described families of RTK regulators are the Leucine-Rich Repeat and Immunoglobulin (Lrig) proteins. However, little is known about Lrig-RTK interactions in neurons or how these inter-actions influence neural circuit assembly and function. The Lrig family consists of three poorly understood transmembrane proteins with homo-logy to molecules that regulate aspects of neuronal development, including cell-adhesion, neurite outgrowth and synapse formation. Unlike other Lrig proteins, Lrig2 is strikingly enriched in differentiating neurons, including motor neurons in the spinal cord, one of the few neuronal populations where there is direct evidence for a role for Lrig signaling. Therefore, the focus of my research is to investigate Lrig function in neurons to further understanding of motor circuitry development. Further knowledge of motor circuitry may accelerate the discovery of therapies for motor control damage caused by disease.
Paul Greer, Ph.D.
Postdoctoral Fellow, S. Robert Datta Lab
Harvard Medical School
A major challenge facing modern neurobiology is to understand how the brain is wired to extract information from the environment and convert that information into appropriate behavioral responses. Functional defects in the neural circuits that couple sensory inputs to effective actions are at the core of many devastating neurological disorders; diseases ranging from anxiety disorder to autism to cerebral palsy are all pathological states in which behavioral responses to environmental stimuli are altered. Although we have an increasingly sophisticated view of how genetic and molecular defects in the nervous system lead to functional alterations in individual neurons, we lack a basic understanding of how neural diseases alter circuit function, which ultimately is the cause of disease. To address this challenge I propose to identify and manipulate the hardwired circuits underlying innate odor-driven avoidance behaviors in the mouse. These circuits are attractive models for studying how sensory information processing is coupled to behavioral outputs as the hardwired nature of these behaviors suggests a relatively simple, and therefore experimentally approachable, connectivity scheme. By fully characterizing an odor-driven avoidance circuit we will have revealed a specific neural substrate upon which both experience and disease can act to alter perception and behavior. This circuit can therefore be used as a platform for testing hypotheses addressing the mechanisms of adaptation and maladaption of neural function.
Rong Luo, Ph.D.
Postdoctoral Fellow, Xianhua Piao Lab
Children’s Hospital Boston
GPR56, an orphan adhesion G protein-coupled receptor, plays an important role in brain development. Mutations in the human GPR56 gene cause a devastating human brain malformation. Affected individuals suffer a constellation of cerebral palsy- related symptoms, including mental retardation and motor developmental delay. Our recent studies in mouse models demonstrate that loss of the Gpr56 gene leads to a severe malformation of the forebrain. However, the cellular and molecular mechanisms through which GPR56 regulates brain development remain unknown. This project is to study the role of GPR56 signaling in brain development. In our preliminary studies, we have identified the ligand of GPR56 in mouse developing brain, and confirmed the specific association between GPR56 and its ligand by standard co-immunoprecipitation experiments. Further studies demonstrated that GPR56 signaling inhibits neuronal migration. We will further characterize the functional interaction of GPR56 and its ligand in cortical development, and reveal the signaling properties of GPR56. The success of the proposed research will shed light on the cellular and molecular mechanisms of brain development and malformation as well as the development of cerebral palsy. The long-term goal of this project is to eventually extend our findings to the prevention and treatment of cerebral palsy.