Professor, Director Molec. and Structural Neurobiol. Gene Therapy Prog. Director Stem Cell SCEF
Bioinformatics; Cell growth, differentiation and development; Epigenetics; Gene Expression; Gene Therapy; Genome Integrity; Genomics and proteomics; Molecular and Cellular Biology; Molecular Basis of Disease; Neurobiology; Signal Transduction; Stem Cells; Transcription and Translation
Google Scholar (10/07/2021)
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The long term mission of our laboratory, which I co-direct with Dr. Ewa Stachowiak, is to understand the principles governing molecular control of neural development, the implications for developmental- and aging-related diseases and the wide ranging effects on brain functions including behavior.
My scientific pursuit began to develop through the years of my graduate training in neuroscience and biochemistry at the Nicolaus Copernicus University and in Gdansk Academy of Medicine in Poland, and later as a postdoctoral trainee with Michael Zigmond and Barry Kaplan at the University of Pittsburgh. I have continued my development into the areas of cell biology, molecular biology and in recent years also genomics to study development and functions of the nervous system. My scientific pursuit has brought number of fundamental discoveries, and new concepts that influenced and often changed how we view the genome, its function, structure and regulations, and how the genome programs organismal development, especially the development of neuronal cells as well as the malformations in neuro-developmental diseases.
I have published several papers assessing mechanisms of neural deficits in animal models of neurodevelopmental and neurodegenerative disorders, particularly of Schizophrenia and Parkinson Disease, and the mechanism underlying recovery after treatment (1974-1989). Over last 30 years my investigations have focused on the integrative mechanisms that operate at the interface of the genomic blueprint (nature) and the stochastic developmental signals (nurture), asking how they may be integrated to underwrite development and what is their potential role in the disease. My studies have illuminated new mechanisms of gene regulation in which extrusions of DNA cruciform (and other 3D structures) induced by DNA supercoiling affect gene promoter interactions with transcriptional factors and constitute a new mechanism that may come to play in gene regulations.
My major discovery was the novel molecular mechanism that operates at the interface of the developmental signals and the genomic information, integrates the epigenomic signals to elicit coordinate regulations of thousands of genes, a process deemed essential for the cell transitions between developmental stages. Our in depth and broad studies lead to the formulation of Integrative Nuclear FGFR1 Signaling (INFS) mechanism for which I was awarded by the SUNY Central. At the center of INFS is a novel nuclear form of FGFR1 which together with its NLS-equipped ligands accumulates directly in the cell nucleus.
We demonstrated that nFGFR1 interacts with the with key nuclear factors under the regulation by a plethora of diverse developmental signals and controls the global gene functions through a Feed Forward End Gate Mechanism (DOI:10.1074/jbc.M504400200). Our investigations using in vitro stem cells cultures, in vivo brain transfers of DNA-nanocomplexes, as well as generated our own transgenic mice, have shown that INFS is a central control module that governs stem cell biology, ontogenic gene regulations and complements and controls other developmental pathways including the Pluripotency and Cell Cycle modules.
My further investigations, using Nextgene sequencing technology for global genome analysis, (RNAseq) and genome protein interactions (ChiPseq), have contributed to the forefront of genome studies at our University. Importantly, they lead us to formulate “Evidence based theory for integrated genome regulation of ontogeny - an unprecedented role of Nuclear FGFR1 signaling”. This novel concept was presented in our publication selected by editor as the leading article in the journal of Cell Physiology (doi: 10.1002/jcp.25298)
and summarized in the Editor’s note - “Construction of a complex functional system, such as a living organism, requires not only raw building materials (genes encoding structural and other functional proteins), but also an assembly program, organized into flexible feedback and feed-forward sub-routines that can function within, and readily adapt to a non-stable environment. While the genetic experiments have positioned the fgfr1 gene at the top of the gene hierarchy that governs gastrulation, as well as the subsequent development of the major body axes, nervous system, muscles, and bones. The discovery of INFS shows that this regulation is executed by a single protein, the nuclear isoform of FGFR1 (nFGFR1), which integrates signals from development-initiating factors and operates at the interface of genomic and epigenomic information. nFGFR1 cooperates with a multitude of Transcriptional Factors, and targets thousands of genes encoding for mRNAs, as well as miRNAs in top ontogenic networks. nFGFR1 binds to promoters of ancient proto-oncogenes and tumor suppressor genes which serve as switches in cell proliferation, binds and regulates the pluripotency core genes as well as metazoan morphogens that delineate body axes, construct the nervous system and the mesodermal and endodermal tissues. The seminal discovery of the pan-ontogenic gene programming by INFS feed-forward and feedback loops impacts our understanding of ontogeny, the roots of cancer, and developmental diseases, and holds new promise for reconstructive medicine, and cancer therapy”.
Further studies in my laboratory pioneered advanced genome-chromatin conformational analyses (3C, HiC, HiChiP) at UB and lead to the formulation of a novel Genome Archipelago Model (GAM) on how the genome’s information is structurally organized and executed (doi: 10.3390/ijms22010347). The GAM offers new insights into how a multitude (hundreds of millions) of intra and interchromosomal interactions form constantly changing archipelagos of the Topology Associated Domains (TADs), islands, which create genomic blueprints for specific tissues and organs and their functions. Results of our investigation assign nuclear FGFR1, in partnership with the DNA architectural protein, CTCF, an important role in organizing TAD islands, and expand on new paradigm for the global genome regulation of neuro-ontogeny. GAM offers a physical basis for the idea of systems genome, in which individual genome elements are integrated into a synchronized ‘organism-like’ entity,” as shown in our studies. Such model helps to understand how isolated mutations could lead to complex genome dysregulations affecting vast regions of genome in developmental disorders or cancer. Our current investigations show an unprecedented model of the genome assembled into highly coordinate Gene Activity Networks or GANs, composed of recurrent motifs, which may underwrite developmental programs. The future challenge, on which we currently embark, will aim to integrate into a unified model the genome structural features and the Gene Activity Networks.
In order to link TADs and GANs to brain development organoids, in collaboration with Drs. Ewa Stachowiak and Yongho Bae (Pathology and Anatomical Sciences) we have adopted and further developed protocols for generating human cerebral organoids and cerebro-vascular organoids (DOI 10.1038/s41398-017-0054-x). The organoids mimic key aspects of the human brain development, reconstitute the multilayer cortex and the underlying germinal-ventricular structures. Using iPSC derived organoids from control individuals and the individuals suffering from schizophrenia, we have shown early neural cell developmental abnormalities leading to cortical malformation in this developmental disorder. Our genomic studies lend support of the schizophrenia water-shed hypothesis of Cannon and Keller (2006), and show that the INFS is the common dysregulated pathway in patients with different schizophrenia linked mutations (DOI 10.1007/978-3-319-93485-3_6). The INFS becomes dysregulated as it integrates the schizophrenia genetic and environmental disturbances (doi.org/10.3389/fncel.2020.00233). Consequently, the dysregulated INFS deconstructs synchronized developmental gene programs including hundreds of nuclear and mitochondrial chromosome genes that encode mitochondrial proteins.
Using Multi-Electrode Assemblies developed in collaboration with Dr. Anirban Dutta (UB BME Department) we have documented the formation of spontaneously active neuronal circuits in brain organoids and their dysregulation in schizophrenia organoids. Our recent study entitled “A proof of concept ‘phase zero’ study of neurodevelopment using brain organoid models with Vis/near-infrared spectroscopy and electrophysiology. Sci Rep 10, 20987 (2020). https://doi.org/10.1038/s41598-020-77929-8, has initiated and outlined an effective path for developing new treatments for neurodevelopmental disorders. One of our tested therapies involved mitochondria targeting drugs to correct the dysregulated neuronal circuits of schizophrenia cerebral organoids. These studies and our technologies have been transferred also to the laboratories in Polish Academy of Sciences. As the Fulbright Chair of Medical Sciences and Distinguished Professor, I have been developing a multi-center, multinational Program for Combating Neurodevelopmental Disorders involving UB, Polish Academy of Sciences. In addition to the research and development of new bioengineering technologies this program includes training of international students in our laboratory at UB as well as visits of the UB students to Polish Academy of Sciences.
To realize the potentials of our discoveries, we have engaged in the development of new light-based tools to control the genome’s 3D structure and functions. Recent major breakthroughs in the photonics and genomics are enabling the control of biological processes through light. By incorporating light-actuated and light-emitting proteins into cells, key biological processes at the single-cell and even sub-cellular level can be controlled in real time. In collaboration with the wireless communication engineers, involving Dr. Josep Jornet at UB and in the Northeastern University (NEU), under the support of three consecutive NSF grants, we have been working towards development of wireless nano-laser platforms for the control of genome. Our recent NSF grant “Control of Information Processing and Learning in Neuronal Networks through Light-mediated Programming of Genomic Network” focuses on the creation of a new subfield of research which we have named Optogenomics- the light-based control of the genome’s structure and function (Doi:10.1109/JPROC.2019.2916055). While the applications of this new paradigm are uncountable, our initial goal is to demonstrate the feasibility of controlling brain development including information processing and learning. By controlling nuclear FGFR1 interactions with its partner CTCF, a chromatin architectural factor, in developing neural stem cells, we influence the genome structure and function and, thereby, attempt to influence the development of neuronal networks. Our long-term goal is to develop an integrated Genome-Neuronal Function Model by integrating the genomic TADs and GANs to the properties of neuronal network using scalable methods.
Together with my associates and trainees I have developed and directed the “Molecular and Structural Neurobiology and Gene Therapy” program which involves scientists from the University at Buffalo (UB), Albany College of Pharmacy, Italy, Poland and Germany. This program has generated several publications and trained numerous students. I have been involved in multiple graduate programs (currently four programs) and have trained several doctoral students who continued successful postdoctoral careers at leading academic institutions including Yale University, Texas Anderson Cancer Center and the University of Michigan at Ann Arbor. I have trained several postdoctoral fellows who became faculty in the US, Poland and in Germany. I have also trained several postdoctoral researchers, master and undergraduate students. I have served as an editor and co-author of the books “Stem Cells - From Mechanisms to Technologies” World Scientific Pub. & Imperial College Press. (December, 2011) and "Human Neural Stem Cells… “, Springer – Nature, 2018, vol. 66 and currently as an editor of the Special Issue of International Journal of Molecular Sciences, Neural Stem Cells Development – Systems Approach. I have published over 125 research papers and lectured on my work to broad national and international communities (>150 -seminars).
In recent years, studies in a number of world leading cancer labs including Dr. Richard Grose (https://doi.org/10.1083/jcb.201108077) of the Cancer Research UK Centre of Excellence, Queen Mary University of London, UK and Dr. Carlos Arteaga of the Harold C. Simmons Comprehensive Cancer Center University of Texas have shown that dysregulation of our discovered INFS pathway plays critical role in cancer, leading to new concepts in the treatment of cancer. In Texas studies (DOI: 10.1158/1078-0432.CCR-17-1232 ; DOI: 10.1158/1078-0432.CCR-20-3905), an amplified nFGFR1 was shown to lead to the activation of Estrogen Receptors, causing the growth of the breast cancer. While being resistant to the estrogen antagonists, tumor growth was be blocked by the FGFR1 inhibitors. The first of the Texas studies referenced our six publications and, more recent study, has employed molecular DNA constructs shared by our laboratory. Similarly independent studies at UB laboratory of Robert Straubinger have pointed out to the dysregulation of the nuclear FGFR1 as a driving mechanism in pancreatic cancer metastasis. These preclinical and clinical studies are exemplary demonstrations on how an advanced basic science leads to the clinical translation and new treatment strategies for malignant cancers. This, I believe, is the highest reward for a scientist.
In summary the main discoveries of my collaborative work with Dr. Ewa K. Stachowiak are: (1) the INFS, (2) the theory of genomic control of ontogeny, (3) the Genome Archipelago Model and, recently (4) the Optogenomics. These discoveries have laid fundaments for the new treatment of breast cancer by targeting FGFR1 receptors and for the treatments of pancreatic cancer and schizophrenia.
Educational Activities and Teaching: I have participated together with the members of our neuroscience community in developing a new Graduate Program in Neuroscience at the SUNY, Buffalo. I am teaching neuroanatomy courses for dental students (ANA811) and for graduate students (NRS524). At present I participate in team-taught graduate courses in Neuroscience and Developmental Neuroscience (NRS 520, 521 and NRS 524). I am serving as a mentor for several undergraduate, graduate (masters and doctoral students) and postdoctoral fellows in the Neuroscience Program, Anatomy and Cell Biology Program and in the IGERT program in the Departments of Chemistry and Engineering. Additionally to mentoring master and Ph.D. students at the UB, I have helped to train graduate students in the University of Camerino (Italy) and Hannover Medical School (Germany). The works of our graduate students have been described in several publications.