Cell growth, differentiation and development; Gene Expression; Molecular and Cellular Biology; Neurobiology; Signal Transduction
The long term mission of my research has been to understand developmental and regenerative processes within the mammalian CNS. Towards these goals I have employed stereological and microscopic imaging techniques, stem cell cultures and in vivo models to analyze brain development, regenerative capacity, etiology of neurodevelopmental and neurodegenerative diseases. I have established a quantitative Neuroanatomy Stereology laboratory within a multi-disciplinary Molecular and Structural Neurobiology and Gene Therapy Program.
Developmental disorder- Schizophrenia
The studies that I have been engaged in the last several years have addressed fundamental aspects of organismal development, their pathological disruptions and their targeting for regenerative medicine. With the advent of multicellular organisms, mechanisms emerged that imposed new controls which limited the natural propensity of organisms composed of single cells to proliferate, and to invade new locales, which ultimately results in the formation of tissues and organs. How such an immense task is accomplished has been largely unknown. Our collaborative studies have revealed a pan-ontogenic gene mechanism, Integrative Nuclear Fibroblast Growth Factor Receptor 1 (FGFR1) Signaling (INFS), which mediates global gene programing through the nuclear form of the FGFR1 receptor (nFGFR1) and its partner CREB Binding Protein, so as to assimilate signals from diverse signaling pathways.
My work, which has contributed to these findings, has been focused on the role of INFS in cellular development. I have shown that INFS is central to the development of neural cells and that pluripotent ESC and multipotent NPCs can be programmed to exit from their cycles of self-renewal, and to undergo neuronal differentiation simply by transfecting a single protein, nFGFR1. Using viral and novel, nanotechnology based gene transfers, I have demonstrated that it is possible to reactivate developmental neurogenesis in adult brain by overexpressing nFGFR1 in brain stem/progenitor cells. We have shown that similar effects can be produced by small molecules that activate the INFS. These findings may revolutionize treatments of abnormal brain development, injury and neurodegenerative diseases by targeting INFS to reactivate brain neurogenesis.
Schizophrenia (SZ) has been linked to the abnormal development of multiple neuronal systems, and to changes in genes within diverse ontogenic networks. Genetic studies have established a link between FGFs and nFGFR1 with these networks and SZ. nFGFR1 integrates signals from diverse SZ linked genes (>200 identified) and pathways[2-6] and controls developmental gene networks. By manipulating nFGFR1 function in the brain of transgenic mice I have established a model that mimics important characteristics of human schizophrenia: including its neurodevelopmental origin, the hypoplasia of DA neurons, increased numbers of immature neurons in cortex and hippocampus, disruption of brain cortical layers and connections, a delayed onset of behavioral symptoms, deficits across multiple domains of the disorder, and their correction by typical and atypical antipsychotics[6, 7].
To understand how SZ affects neural development, I have begun to generate induced pluripotent stem cells (iPSCs) using fibroblast of SZ patients with different genetic backgrounds. In my studies I employ 3-dimensional cultures of iPSCs, co-developmental grafting of the iPSCs neural progeny into murine brain, FISH (Fluorescent In Situ Hybridization), gene transfer and quantitative stereological analyses. I am testing how genomic dysregulation affects the developmental potential of schizophrenia NPCs (formation of 3D cortical organoids, in vivo development of grafted iPSCs) which may be normalized by correcting nFGFR1 and miRNA functions. In summary, my studies are aimed to develop to new treatments for Schizophrenia and other neurodevelopmental disorders including potential preventive therapies.
Effect of maternal diet and metabolic deficits on brain development (collaboration with Dr. Mulchand Patel, Department of Biochemistry, UB)
Approximately 36% of the adults in the US are classified as obese. Available evidence from epidemiological and animal studies indicate that altered nutritional experiences early in life can affect the development of obesity and associated metabolic diseases in adulthood and subsequently in the offspring of these people. Furthermore, there is an increased risk for mental health disorders that is associated with these conditions. Our studies show that an altered maternal environment in female rats produced by consuming a high fat (HF) or high sugar diet (HS) negatively impacts the development of brain stem cells and fetal brain circuitry in the offspring[8, 9]. Increased numbers of immature, underdeveloped neurons are found in the hypothalamus, which controls feeding behavior. Similar changes are found in areas of the cerebral cortex involved in other diverse behavioral functions. These changes reveal an alarming predisposition for neurodevelopmental abnormalities in the offspring of obese female rats.
Blast induced brain injury and regeneration (collaboration with Dr. Richard Salvi, Department of Communicative Disorders and Sciences, UB)
Sound blast induced brain injury is a major concern in military exposure to excessive noise. In mice exposed to the sound blast we found marked loss of myelinated fibers and neuronal apoptosis in brain cortex. These degenerative changes were accompanied by increased proliferation of brain neural progenitor cells in the subventricular zone of the lateral ventricles. Immunohistochemical and stereological analyses reveal that these initial changes are followed by the gradual reappearance of myelinated cortical fibers. This is accompanied by increased proliferation of oligodendrocytic progenitors. I found that these progenitors also differentiate to mature oligodendrocytes in brain cortex. Our findings show that the blast-induced activation of the brain neural stem/progenitor cells generates predominantly new oligodendrocytes. The capacity of these new cells to myelinate damaged and regenerating neurons will be addressed in my planned future investigation.