2017 — 2021 |
Fancy, Stephen Philip James |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Vasculature Provides the Substrate For Oligodendrocyte Progenitor Migration in Development and Disease @ University of California, San Francisco
PROJECT SUMMARY/ ABSTRACT In demyelinating diseases such as multiple sclerosis (MS) and Periventricular Leukomalacia associated with Cerebral Palsy (CP), myelin sheaths are lost through injury or death of oligodendrocytes (OL). Remyelination by oligodendrocyte precursor cells (OPCs) is considered crucial to recovery, but myelin repair often fails contributing significantly to ongoing neurological dysfunction, axonal loss and disease progression. There are currently no therapies to promote remyelination, and one of the greatest unmet needs is gaining a greater understanding of the obstacles to successful myelin repair. Remyelination can be divided into two critical stages: Firstly (1) recruitment of migrating OPCs into areas of demyelination from surrounding normal appearing white matter followed by (2) their differentiation into mature OL within the lesion. We have recently identified that OPCs migrate during their developmental dispersal around the CNS using vasculature as a physical scaffold for motility (Science 351, 379 (2016)). This requires movement along vessels, but also subsequent detachment from vasculature after migration to allow OPC differentiation. The mechanism of migration of OPCs into remyelinating lesions, critical for successful myelin repair, remains largely unclear. This grant will (1) identify for the first time how OPCs are recruited into remyelinating lesions utilizing vasculature as a physical scaffold for motility. It will (2) demonstrate that failure of OPCs to detach from vasculature appropriately is a pathological finding in human white matter injury. It will identify this inability to detach not only as a mechanism preventing their proper distribution into lesions but also as an obstacle for subsequent OPC differentiation. (3) It will show that OPCs remaining inappropriately attached to vessels interfere with astrocyte-vascular coupling and integrity of the blood brain barrier that may contribute further to lesion pathology.
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0.936 |
2020 — 2021 |
Fancy, Stephen Philip James |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Oligodendroglial Intrinsic Ring Finger Protein Family Members Are Injury Specific, But Not Developmental, Regulators of Oligodendrocyte Maturation @ University of California, San Francisco
PROJECT ABSTRACT: Permanent damage to white matter tracts, comprising axons and myelinating oligodendrocytes (OL), is an important component of Multiple Sclerosis (MS) in adults, as well as brain injuries of the newborn that cause cerebral palsy and cognitive disabilities. However, regulatory factors relevant in human developmental myelin disorders and in myelin regeneration are unclear. In both conditions, damaged myelin sheaths can be regenerated by oligodendrocyte precursors (OPCs) that are recruited to lesions and differentiate in a process called remyelination. But this myelin regenerative response often fails [1, 2], and contributes significantly to ongoing neurological dysfunction, axonal loss and disease progression, and it is critical to understand mechanisms underlying this failure of endogenous injury repair in humans. Much has been learnt about the regulation of oligodendrocyte biology in remyelination from the study of development, and indeed the recapitulation hypothesis of myelin regeneration proposes that mechanisms that underlie remyelination after injury are essentially a rerunning of a developmental myelination program [3]. However, human myelin repair is highly susceptible to failure, despite the robustness of developmental myelination, suggesting key differences in the regulation of the two processes. Little is understood about whether there are oligodendroglial intrinsic factors that operate specifically in the setting of injury but not in development, and how these might become dysregulated. Here we identify oligodendroglial intrinsic Ring Finger Protein family members as injury specific regulators of oligodendrocyte maturation kinetics, that do not function in development but are critical for remyelination, uncovering key regulatory differences between the OL intrinsic program of developmental myelination and regeneration. In this grant, we will 1) identify the functions of Ring Finger Family members RNF43 (Ring Finger Protein 43) and ZNRF3 (Zinc and Ring Finger 3) in development and injury in OL lineage, showing that they function to regulate OPC maturation kinetics only in the setting of injury, 2) identify how they are regulated in OL lineage, and demonstrate that RNF43 is a marker that identifies activated OPCs responding to injury in human MS lesions, 3) identify their function to repress Wnt signaling via regulation of surface presentation of specific Frizzled receptor family members on OPCs, and that small molecule manipulation of a Frizzled signaling axis can be used to promote myelin regeneration.
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0.936 |
2020 — 2021 |
Fancy, Stephen Philip James |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Project 2: Mechanisms Underlying Oligodendrocyte Precursor-Mediated Angiogenesis and Interneuron Vessel-Associated Migration in Human Neonatal Brain @ University of California, San Francisco
Project 2 Abstract Circuit formation in developing human brain involves sequential steps of: (i) cell fate specification, (ii) proliferation and regulation of precursor pool size, and (iii) migration of neural cells to their appropriate position to integrate into local circuits. Young interneurons (IN) and oligodendrocyte precursors (OPCs) persist as immature yet committed lineage cells for a protracted period of time during development, undergoing extensive migration and late differentiation before integration into/and myelination of neural circuits in human developing brain. This relatively long developmental time course means that they may be more vulnerable to neonatal injury. Our findings in the prior cycle of this program highlighted novel stromal interactions of OPCs and IN with blood vessels during development. We identified that OPCs use vasculature as a physical scaffold for migration in the developing CNS (Tsai Science 2016 PMC5472053), that OPCs drive white matter angiogenesis in mouse brain (Yuen Cell 2014 PMC4149873), and that migrating clusters of interneurons associate with the vasculature in the human brain (Paredes Science 2016 PMC5436574). However, very little is understood about the cellular and molecular mechanisms that underlie human OPC induced angiogenesis and IN perivascular migration, a phenomenon unique to human brain development. What are the cellular mechanisms that underlie angiogenesis directed by OL lineage in human brain? And how does the establishment of a vascular scaffold subsequently mediate and regulate IN sub-type migration? This project seeks to understand mechanisms underlying these processes in human neonatal brain. We will 1) evaluate factors involved in OPC interaction with endothelial tip cells as well as the morphological interaction, identify candidate angiogenic pathways and novel tip cell markers in human brain, and investigate dysfunction of OPC-tip cell interactions in human neonatal hypoxic injury. We will 2) determine a functional role for OPC-encoded Wnt and VEGF ligands in orchestrating endothelial tip cell angiogenesis and in resilience to hypoxic injury, and we will 3) identify the transcriptomic signature of vessel- associated migrating IN in human neonatal brain, and determine whether diversity of vessel associated versus non-vessel associated IN migration is a reflection on their developmental origin. Understanding the cellular mechanisms mediating OPC-mediated angiogenesis and IN vessel-associated migration in human brain will not only elucidate fundamental biological processes, but will provide insight into how dysregulation could occur in preterm birth and term hypoxia and provide perspective for the planning for therapeutic interventions.
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0.936 |