During her postdoctoral training in Dr. Ulrich Steidl's laboratory in the Department of Cell Biology at the Albert Einstein College of Medicine, Dr. Will has independently and successfully initiated a line of research focusing on the molecular regulation of adult tissue-specific stem cell self-renewal and differentiation commitment. Her work has uncovered a novel central role for a particular transcription factor, Special AT- rich sequence-binding protein 1 (Satb1), in the maintenance of gene expression programs and DNA cytosine methylation patterns, which govern hematopoietic stem cell (HSC) function. Under the guidance of her mentoring committee and with the help of carefully selected and dedicated expert collaborators and advisers, Dr. Will will focus on reaching her short-term career goals for the duration of the award. Her proposal is thus tailored to meet the following specific experimental research and associated training objectives: * To identify and functionally test Satb1-dependent gene networks, particularly the ones regulating myeloid and lymphoid differentiation commitment of HSCs and to evaluate their contribution to age-related myelodysplastic syndrome; * To assess the requirement for myeloid-biased HSCs in the pathogenesis of aging and in aging- associated myelodysplasia using murine models and human primary cells; * To extend her experience in designing and conducting RNA isolation, chromatin immunoprecipation and DNA cytosine methylation detection followed by deep sequencing using primary HSCs and HSC cell lines; and to get profound training in the computational analysis of NGS data analysis; * To foster existing and establish new collaborations, especially in the field of aging research; * To generate exciting data suitable to produce grant proposals; * To obtain independent R01(-type) funding at the end of the award. In order to meet these milestones, the candidate will take advantage of the outstanding state-of-the-art research and training environment at the Albert Einstein College of Medicine, both at the departmental and the institutional level, and of well-established ongoing collaborative efforts of Dr. Steidl and several established investigators at other New York City-based institutions. This is made possible through the retention of Dr. Will as a junior, non tenure-track faculty member in the Department of Cell Biology for the next five years. Dr. Will will advance her focused training for developing her independent research by engaging in one-on-one meetings with her mentors and collaborators, relevant coursework, scientific research seminars and symposia, intra-and extra-institutional career development and grant writing workshops. Additionally, she will profit greatly from speaking opportunities at her and other NYC-based institutions, and at scientific meetings. Upon completion of the award, the candidate will be able to address her long-term career goals, which are: * To establish a long-term research program addressing relevant questions in the fields of stem cell and aging research; * To further build her own research group and to obtain a position as an independent investigator at an academic institution. To this end, acquired and further strengthened abilities under the K01 award will provide Dr. Will with the critically needed conceptual and technical framework to successfully establish her independent research pipeline. Ultimately, Dr. Will's research will provide a much more profound understanding of the gene expression-regulating and potentially reversible processes underlying stem cell aging, which can be leveraged for fundamentally novel therapeutic approaches in hematopoietic stem cell-derived disorders in the elderly.

Public Health Relevance

Adult stem cells play a pivotal role in the homeostasis and repair processes of tissues throughout life and are also often the cellular source for aging, and aging-associated disorders. Understanding the precise genetic and epigenetic mechanisms by which sustained stem cell function is established, maintained and compromised will ultimately advance our options to develop innovative, and highly specific therapeutic interventions for a multitude of diseases. The herein proposed training plan will advance our incomplete understanding of the transcriptional regulation of hematopoietic stem cell fate instruction and could serve as a new paradigm for many tissue-specific stem cells; it will also allow Dr. Will the extension of her training and expertise in assessing aging-related pathomechanisms using next generation sequencing data analysis and the integration of murine and human models for the functional study of age-related genetic alterations.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Scientist Development Award - Research & Training (K01)
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Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
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Bishop, Terry Rogers
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Albert Einstein College of Medicine
United States
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Carvajal, Luis A; Neriah, Daniela Ben; Senecal, Adrien et al. (2018) Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia. Sci Transl Med 10:
Pietras, Eric M; Mirantes-Barbeito, Cristina; Fong, Sarah et al. (2016) Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal. Nat Cell Biol 18:607-18